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Abstract Portal vein thrombosis (PVT) worsens the long-term prognosis of patients with cirrhosis; however, the optimal treatment remains to be determined. Reports on the efficacy of direct oral anticoagulants are increasing, and further evidence is needed. Therefore, we investigated the effectiveness of treatment with edoxaban in patients with PVT. We retrospectively reviewed the outcomes of edoxaban and warfarin as antithrombotic therapies for PVT. The median overall survival time was 4.2 years in patients with PVT, with a 1-year survival rate of 70.7% and a 5-year survival rate of 47.9%. The leading cause of death was hepatocellular carcinoma. The overall response rate for thrombolysis in the edoxaban group was 76.7% compared to 29.4% in the warfarin group, and edoxaban significantly improved PVT compared to warfarin. In addition, edoxaban provided long-term improvement of PVT. Warfarin, on the other hand, was temporarily effective but did not provide long-term benefits. The Child–Pugh and albumin-bilirubin scores did not change after edoxaban or warfarin use. No deaths occurred due to adverse events associated with edoxaban or warfarin. Edoxaban as a single agent can achieve long-term recanalization without compromising the hepatic reserves. Edoxaban is easy to initiate, even in an outpatient setting, and could become a major therapeutic agent for the treatment of PVT.

Background/Aims Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. Methods This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. Results Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P

Abstract Background Hepatocellular carcinoma (HCC) in autoimmune hepatitis (AIH) was considered rare but is increasing with prolonged prognosis. Its impact on the overall prognosis of AIH is unknown, and treatment has not been established. Aim To investigate the risk factors and prognosis of HCC in patients with AIH and identify appropriate management strategies. Methods We studied patients with AIH including background liver disease, sex, age, complications, treatment, response to treatment, liver fibrosis, prognosis, and treatment. Results In 131 patients, deaths due to liver failure were more common early after the onset of AIH; however, deaths due to HCC increased gradually. HCC was observed in 12 patients (median age, 70 years; male/female, 4/8; cirrhosis at onset, 11; median time to carcinogenesis, 7 years). Cirrhosis at diagnosis was identified as a risk factor for carcinogenesis in the multivariate analysis (odds ratio, 41.36; p

Background and Aims: The clinical characteristics and risk factors involved in the development of liver fibrosis in the subtypes of steatotic liver disease (SLD) remain unknown. We examined the clinical characteristics of SLD subtypes using a large Japanese cohort. Methods: We performed a cross-sectional analysis (total n = 108,446). In this cohort, SLD was diagnosed by ultrasonography. Individuals with none of the cardiometabolic risk factors were excluded. Results: According to their nonalcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) status based on the database, participants with cardiometabolic criteria were allocated to the MASLD, MASLD with increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD) with metabolic dysfunction groups. Of 30,857 subjects with SLD, 21,488 (69.6%) had NAFLD, and 20,922 (67.8%) had MASLD. There were few differences in the clinical characteristics between NAFLD and MASLD. After adjustment for clinical variables, we found that male patients with MetALD [odds ratio (OR) 2.26; 95% confidence interval (CI) 1.87–2.84] and ALD with metabolic dysfunction (OR 3.92; 95% CI 2.85–5.39) had a significantly higher risk for advanced liver fibrosis (diagnosed by Fibrosis-4 (FIB-4) index >2.67) compared to those with MASLD. In female patients with ALD, metabolic dysfunction (OR 5.80; 95% CI 2.51–13.4) and systemic blood pressure of ≥130 mmHg were significant risk factors for high FIB-4 (males: OR 3.38, 95% CI 2.51–4.55; females: OR 4.34, 95% CI 2.66–7.07, P < .001). Conclusion: Alcohol intake and systolic blood pressure are independent contributors to liver fibrosis progression assessed by FIB-4 in SLD.

Abstract Alcohol abuse is associated with several diseases, such as hepatocellular carcinoma, cirrhosis, and extrahepatic malignancies. Recently, we reported albumin platelet product (APP) and modified APP (mAPP) as novel indices of liver fibrosis staging and prognosis in patients without alcoholic liver diseases. This retrospective cohort study aimed to extend application of APP and mAPP in prognosis prediction of patients with alcoholic liver diseases. We enrolled 222 patients with alcoholic liver diseases based on their medical records. Cut-off values of APP = 4.349 and mAPP = 2.484 were adopted based on a past report. Hazard ratios of APP and mAPP were compared to those of albumin-bilirubin score and fibrosis-4 index. The primary and secondary endpoints were carcinogenesis and death, respectively. Thus, APP = 4.349 and mAPP = 2.484 significantly differentiated cancer-free survival and overall survival in univariate analysis. Hazard ratios of mAPP = 2.484 were greater than those of the albumin-bilirubin score of -2.270 and fibrosis-4 index of 3.25. Multivariate analysis revealed mAPP = 2.484 as an independent risk factor for carcinogenesis and overall death. In conclusion, mAPP is a simple index to stratify patient’s risk for carcinogenesis and death.

Abstract Hepatocellular carcinoma invasion of the bile duct is rare and has a poor prognosis. A 77‐year‐old man presented at the emergency department with persistent pain in the right hypochondrium. Blood tests and imaging studies revealed a 70‐mm occupying lesion in the right lobe of the liver and dilated intrahepatic bile ducts. He was diagnosed with obstructive jaundice and cholangitis. Imaging studies showed an internal mass with poor contrast effects. A liver biopsy was performed to confirm the diagnosis and hepatocellular carcinoma was suspected. Endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, and peroral cholangioscopy were performed to determine the treatment strategy. The bile duct invasion did not extend to the porta hepatis; therefore, right hepatic lobectomy and radical resection were performed. Bile duct invasion in hepatocellular carcinoma is rare and often difficult to diagnose by computed tomography or conventional endoscopic retrograde cholangiopancreatography. However, endoscopic ultrasound and peroral cholangioscopy enable safe and accurate diagnosis of the extent of invasion.

Neuroprotective therapeutic potential for restoring dysregulated microRNA (miRNA) expression has previously been demonstrated in a gerbil cerebral infarction model. However, since temporal changes in miRNA expression profiles following stroke onset are unknown, miRNAs proving to be useful therapeutic targets have yet to be identified. We evaluated cognitive function, hippocampal neuronal cell death, and microarray-based miRNA expression profiles at 5, 9, 18, 36, and 72 h after 5-min whole brain ischemia in gerbils. A decline in cognitive function occurred in parallel with increased neuronal cell death 36–72 h after ischemia. The Jonckheere-Terpstra test was used to analyze miRNA expression trends 5–72 h after ischemia. The expression levels of 63 miRNAs were significantly upregulated, whereas 32 miRNAs were significantly downregulated, monotonically. Of the 32 monotonically downregulated miRNAs, 18 showed the largest decrease in expression 5–9 h after ischemia. A subset of these dysregulated miRNAs (miR-378a-5p, miR-204-5p, miR-34c-5p, miR-211-5p, miR-34b-3p, and miR-199b-3p) could be associated with brain ischemia and neuropsychiatric disorders.

Abstract Aim Indications of drug therapies to elderly patients with hepatocellular carcinoma (HCC) should be carefully determined. The current study assessed the safety and efficacy of molecular targeted agents (MTAs) in the elderly patients with HCC, and identified factors associated with prognosis in a real‐world clinical setting. Methods In a retrospective observational study, clinical data of patients with unresectable HCC treated with sorafenib or lenvatinib as first‐line treatment at our hospital between 2011 and 2022, were investigated. Clinical parameters, therapeutic effects, adverse events (AEs), and prognosis were evaluated separately for the non‐elderly (

Abstract Background and Aim Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome. This study was performed to examine the association between NAFLD and each factor of metabolic syndrome and to identify the factors that are most strongly associated with NAFLD in participants undergoing health checkups. Methods We studied 6538 participants who underwent a health checkup from 2017 to 2018 in our institution. Participants with alcohol intake exceeding 20 g/day or with other chronic liver diseases were excluded. Fatty liver was detected by ultrasonography. Results In total, 4310 participants were enrolled, and 28.4% had fatty liver (NAFLD). The prevalence of NAFLD was highest in the diabetes mellitus (DM)‐only group than in the dyslipidemia‐only or hypertension‐only group. The DM‐only group was the only group whose prevalence of NAFLD was >50% in the overall study and in males. The prevalence of NAFLD was higher in males than in females in the DM‐only, hypertension‐only, and dyslipidemia‐only groups. The prevalence of NAFLD was >70% in the dyslipidemia and DM combined group. Multivariate analysis showed that gender and HbA1c were the independent factors most strongly associated with NAFLD. The cutoff value for HbA1c by receiver operating characteristic curve analysis was 5.8% (sensitivity, 57.9%; specificity, 72.6%; area under the curve, 0.70). Conclusion NAFLD was most strongly associated with DM, among the various components of metabolic syndrome. We strongly recommend abdominal ultrasonography to detect NAFLD in patients with an HbA1c of ≥5.8% in general practice and during health checkups.

Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.

Abstract Aim We analyzed the association between the modified albumin–bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u‐HCC). Methods In this retrospective observational study, we included 71 u‐HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. Results According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression‐free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second‐line treatment with multi‐targeted agents was also significantly higher in the mALBI 1+2a group. Conclusions In real‐world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u‐HCC patients with mALBI 1+2a.

Background and Aims: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. Methods: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin–bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. Results: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6–402.0) and 110.3 (95% CI, 16.3–2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7–199.8) and 93.1 (95% CI, 16.3–1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. Conclusion: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.

Abstract Background The recently developed endoscopic full-thickness resection technique requires reliable closure. The main closure methods are the purse-string suture (PSS) technique and over-the-scope clip (OTSC) technique; however, basic data on the closure strength of each technique are lacking. This study was performed to compare the closure strengths of these two methods in an ex vivo porcine model. Methods In the traction test, a virtual 5-cm full-thickness closure line was closed by the following six methods three times each: conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture. The primary endpoint was the tension at the starting point of dehiscence, measured in Newtons (N) by an automatic traction machine. In the leak test, a 15-mm gastric full-thickness defect was closed by PSS or OTSC six times each, and the closed stomach was then pressurized in a water container. The primary endpoint was the leak pressure when air bubbles appeared. The secondary endpoints were the procedure time and presence of complete inverted closure. Results The mean tension was 2.16, 3.68, 5.15, 18.30, 19.30, and 62.40 N for conventional hemoclips, mucosal PSS, seromuscular PSS, mucosal OTSC, seromuscular OTSC, and surgical suture, respectively. Complete inverted closure was observed for seromuscular PSS, seromuscular OTSC, and surgical suture. The mean leak pressure was 13.7 and 24.8 mmHg in the PSS and OTSC group, respectively (P

Abstract Objectives In the midst of the coronavirus disease 2019 (COVID‐19) infection pandemic, practitioners who perform endoscopic examinations need to prevent infections through procedures, along with routine medical care. By using continuous suction, Endo barrier is thought to be effective in preventing the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) droplets and aerosols. The study aimed to evaluate patient discomfort and satisfaction with the use of the Endo barrier during esophagogastroduodenoscopy (EGD). The study evaluated the system's effectiveness as well as the system's preparation time and the amount of burden on the medical staff. Methods EGD was performed on 788 consecutive cases using the Endo barrier. A questionnaire was used to survey patients after the procedure on four points: discomfort (feeling of pressure, breathlessness) and good points (feeling of relief and satisfaction) using a visual analog scale. In addition, patients were divided into two groups according to sedation status: with sedation (69.7%) and without sedation (30.3%), and their scores were compared. Additionally, the preparation time of the Endo barrier was measured. Results Patient discomfort was reported as minimal, resulting in a high level of satisfaction using this system. Although the overall results were better in the sedation group, the overall evaluation of the non‐sedated group was also favorable. Furthermore, preparation time (30 s) was less burdensome for medical staff. Conclusion The Endo barrier is an easy‐to‐implement tool to prevent COVID‐19 infection in private clinics, and both patients and staff were highly satisfied with the device with or without the use of sedation during EGD.

Abstract Background and Aim This study aimed to investigate the relationship between the histological type of colorectal lymphoma and its endoscopic features. Methods We retrospectively analyzed patients with primary colorectal lymphoma who were diagnosed using colonoscopy and biopsy specimens at the National Cancer Center Hospital, Tokyo, Japan. The lesions were macroscopically classified into the following types via colonoscopy: polypoid, ulcerative, multiple lymphomatous polyposis, diffuse, and mixed. Results A total of 117 lesions were identified in 90 patients enrolled in this study. Of these, 59 (50%) were located in the ileocecal region, 23 (20%) in the rectum, 9 (8%) in the transverse colon, 8 (7%) in the sigmoid colon, 7 (6%) in the descending colon, and 4 (3%) in the ascending colon. Moreover, the most common histological subtypes were diffuse large B‐cell lymphoma (DLBCL) in 39 patients (43%) and mantle cell lymphoma (MCL) in 23 patients (26%), followed by follicular lymphoma (FL; 17%), mucosa‐associated lymphoid tissue (MALT) lymphoma (9%), peripheral T‐cell lymphoma‐NOS (2%), monomorphic epitheliotropic intestinal T‐cell lymphoma (MEITL; 2%), and Burkitt lymphoma (1%). More than half of the DLBCL (52%), MCL (52%), and MALT (56%) lymphomas were macroscopically classified as polypoid types. In contrast, FL lesions showed various macroscopic types. The majority of DLBCL (62%) and FL (78%) lesions were distributed in the ileocecal region. MCL lesions tended to be widely spread in various sites of the large intestine. Conclusions Colorectal lymphomas showed macroscopically distinctive features depending on the histological type. Understanding the macroscopic classification of the lesions by colonoscopy and its distribution may be helpful in diagnosing the type of lymphoma and determining the malignant grade based on the histological types.

Background: The over-the-scope clip (OTSC) is a highly effective clipping device for refractory gastrointestinal disease. However, Japanese data from multicenter studies for anastomotic leakage (AL) involving a secondary fistula after gastrointestinal surgery are lacking. Therefore, this study evaluated the efficacy and safety of OTSC placement in Japanese patients with such conditions. Methods: We retrospectively collected data from 28 consecutive patients from five institutions who underwent OTSC-mediated closure for AL between July 2017 and July 2020. Results: The AL and fistula were located in the esophagus (3.6%, n = 1), stomach (10.7%, n = 3), small intestine (7.1%, n = 2), colon (25.0%, n = 7), and rectum (53.6%, n = 15). The technical success, clinical success, and complication rates were 92.9% (26/28), 71.4% (20/28), and 0% (0/28), respectively. An age of 7 days (84.2%), and the use of simple suction (78.9%) and anchor forceps (80.0%) were associated with higher clinical success rates. Conclusion: OTSC placement is a useful therapeutic option for AL after gastrointestinal surgery.

Abstract Fibrosis-4 index, a conventional biomarker for liver fibrosis stage, is confounded by age and hepatitis activity grade. The current retrospective multicenter study aimed to formulate the novel indices of liver fibrosis by mathematically combining items of peripheral blood examination and to evaluate ability of prognosis prediction. After a novel index was established in a training cohort, the index was tested in a validation cohort. Briefly, a total of 426 patients were enrolled in a training cohort. Albumin and platelet most strongly correlated to fibrosis stage among blood examination. Albumin platelet product (APP) = Albumin × platelet/1000 could differentiate the four stages of liver fibrosis (p

Abstract Background Inflammatory nutritional factors, such as the neutrophil/lymphocyte ratio (NLR), Glasgow Prognostic Score (GPS), modified GPS (mGPS), and C-reactive protein/albumin (CRP/Alb) ratio, have prognostic values in many types of cancer. In this study, the prognostic values of inflammatory nutritional scores were evaluated in the patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant chemoradiotherapy (NACRT). Methods A total of 49 patients who underwent pancreatectomy after NACRT from September 2009 to May 2016 were enrolled. The NACRT consisted of hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) delivered 5 days/week for 2 weeks before pancreatectomy. Inflammatory nutritional scores were determined before and after NACRT in this series. Results The median NLR increased after NACRT (from 2.067 to 3.302), with statistical difference (p

Abstract Aims/Introduction Clinical studies have shown that treatment with inhibitors of sodium–glucose cotransporter 2 (SGLT2) significantly increases the hematocrit in patients with type 2 diabetes. To investigate whether SGLT2 inhibitors directly promote erythropoietin production independently on blood glucose reduction, the hematopoietic effect of the specific SGLT2 inhibitor, luseogliflozin, was examined in non‐diabetic rats with renal anemia. Materials and Methods Renal anemia was induced by treatment with adenine (200 or 600 mg/kg/day, orally for 10 days) in non‐diabetic Wistar–Kyoto or Wistar rats, respectively. Luseogliflozin (10 mg/kg bodyweight) or vehicle (0.5% carboxymethyl cellulose) was then administered for 6 weeks. The hematocrit and the hemoglobin (Hb), blood urea nitrogen, plasma creatinine, and plasma erythropoietin levels were monitored. Results Treatment with adenine decreased the hematocrit and the Hb level, which were associated with increases in the blood urea nitrogen and plasma creatinine levels. In Wistar–Kyoto rats treated with 200 mg/kg/day adenine, administration of luseogliflozin induced glycosuria, but did not change the blood urea nitrogen, plasma creatinine levels, hematocrit, Hb or plasma erythropoietin levels. Similarly, luseogliflozin treatment failed to change the hematocrit or the Hb levels in Wistar rats with renal anemia induced by 600 mg/kg/day of adenine. Plasma erythropoietin concentrations were also not different between luseogliflozin‐ and vehicle‐treated rats. Similarly, in human erythropoietin‐producing cells derived from pluripotent stem cells, luseogliflozin treatment did not change the erythropoietin level in the medium. Conclusions These data suggest that SGLT2 inhibitor fails to exert hematopoietic effects in non‐diabetic conditions.

Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 μg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.

Computed tomography (CT) is often used in the diagnosis of sarcopenia. In this study, we validated the assessment of sarcopenia by the psoas muscle volume using versatile software. The study involved a retrospective analysis of data from 190 patients with liver disease who underwent grip-strength testing and abdominal pelvic computed tomography. To assess sarcopenia, SYNAPSE 3D was used to obtain the skeletal muscle index, the psoas muscle index (PMI), and the simple method. We also used the recently proposed PMI cutoff values, for which the usefulness has been evaluated (O-PMI). The cutoff value of the psoas muscle volume index (PMVI) was determined using one of the diagnostic methods as the gold standard. All diagnostic methods showed that patients with sarcopenia had shorter survival, with O-PMI having the highest hazard ratio (HR) (HR, 6.12; 95% confidence interval [CI], 2.6–14.41; p < 0.001). Even when sarcopenia could not be diagnosed by O-PMI, low PMVI was associated with shorter survival (HR, 3.53; 95% CI, 1.34–9.32; p = 0.01). PMVI may be useful in the evaluation of sarcopenia, including the identification of poor overall survival in cases that cannot be diagnosed by O-PMI, which is considered more useful than PMI.

Abstract Eradication therapy of Helicobacter pylori may be safe if hemin has been intravenously administered in advance, even in patients with a history of recurrent acute porphyria attack.

Abstract Cutaneous metastases from hepatocellular carcinoma (HCC) are rare and mostly occur on the face, scalp, chest, and shoulders, often with rapid growth. We report the case of an 86‐year‐old man who presented to our hospital with a mass, 5 cm in diameter, on the left side of his nose. His past history included a partial hepatectomy for HCC, 3 years previously, and a subsequent diagnosis of lung metastases. Skin and gingival biopsies confirmed the diagnosis of metastatic HCC and he was treated with immunotherapy followed by transarterial embolization (TAE). The latter resulted in a significant reduction in the cutaneous tumour mass.

We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria. Keywords: LCZ696, Proteinuria, Diabetic kidney disease (DKD)

Abstract Background The perioperative factors predicting or influencing early pancreatic ductal adenocarcinoma recurrence are unclear. This study attempted to identify the predictive factors for early pancreatic ductal adenocarcinoma recurrence post-pancreatectomy and the influence of pre- and post- operative adjuvant therapy. Methods One hundred and fifteen patients undergoing curative resection for pancreatic ductal adenocarcinoma between 2000 and 2016 at our institution were retrospectively analyzed. Patients were divided into two groups: those who did (n = 34) and did not (n = 81) experience a recurrence within 6 months postoperatively. Results Multivariate analyses demonstrated postoperative CA19–9 de-normalization, no postoperative adjuvant chemotherapy, and serosal invasion were independent risk factors for early recurrence (P

Background and study aims Exposed endoscopic full-thickness resection (EFTR) enables the operator to obtain a sufficient surgical margin. However, insufflation leakage and secure endoscopic full-thickness closure (EFTC) remain problematic. This study aimed to evaluate the safety and feasibility of a new exposed EFTR. Patients and methods Exposed EFTR was performed for 2-cm virtual lesions in different locations of the upper stomach in four dogs. EFTR mainly involved half-circumferential EFTR of the endpoint and clip-line traction. Pulley traction was applied with the forward approach for the greater curvature. EFTC involved endoscopic ligation with O-ring closure to diminish insufflation leakage, followed by over-the-scope clip closure. Results Complete resection and technical success were achieved in all four cases. One case of intraoperative bleeding was endoscopically managed. No postoperative complications occurred in any cases. The median maximum resected size was 27.5 mm. The median procedure time of the total operation, EFTR, and EFTC was 76, 37, and 35.5 minutes, respectively. The 1-month survival rate was 100 %. Conclusions This therapeutic strategy may lead to the establishment of exposed EFTR.

We sought to identify the frequencies of presarcopenia, sarcopenia, and sarcopenic obesity in patients with nonalcoholic fatty liver disease (NAFLD) and to cross-sectionally determine the nutritional and dietary factors associated with loss of skeletal muscle mass in such patients. Dietary and body component changes produced by a diet intervention were longitudinally investigated. Forty-six NAFLD patients (24 males and 22 females) were enrolled. A second diet treatment was performed at 6 months after entry in 19 of the enrolled patients (6 males and 13 females). Body compositions and dietary nutrients at six months later were compared with those at entry. Three of the 24 (13%) males and four of the 22 (18%) females fulfilled the criteria for presarcopenia and one (5%) female NAFLD patient was in the criteria for sarcopenia at baseline. None of the patients were in the criteria for sarcopenic obesity. The factors associated with skeletal muscle index in the males were body mass index (BMI), insulin-like growth factor-1, total energy intake, and lipid intake, but only BMI and bone mineral density in females at baseline. The diet intervention decreased the skeletal muscle mass in the 6 males by decreasing the total energy intake via lower protein and lipid intakes and improved their liver dysfunction. In the 13 females, a decrease in total energy intake via lower carbohydrate and lipid intake did not change the skeletal muscle mass. These results suggest that loss of skeletal muscle mass is frequently observed in nonobese NAFLD patients and that the frequency of sarcopenic obesity seems to be rare in NAFLD patients. The nutritional and dietary factors that regulate loss of skeletal muscle mass were distinct between our male and female NAFLD patients. Thus, the skeletal muscle mass of such patients as well as their body weight and liver function should be monitored during diet interventions.

Background/Aims: Galectin-9 is a soluble immune modulator with versatile functions, including a role as an immune checkpoint molecule. Therefore, the amount of galectin-9 in the blood may reflect an individual’s immunological balance. Many studies have conducted galectin-9 measurements; however, the reported galectin-9 concentration in the blood varies greatly, even within healthy controls. This study investigates the variation between the reported and actual concentrations of galectin-9. Methods: A GalPharma ELISA and an R&D Systems ELISA kit were directly compared using the same set of plasma and a series of recombinant galectins, including degraded galectin-9. Furthermore, galectin-9 in plasma was concentrated using anti-galectin-9 antibody-conjugated beads, and subjected to western blotting to estimate the quantity and integrity of galectin-9 and assess the consistency of ELISA measurements. Results: The R&D Systems’ ELISA indicated a 50-fold higher median concentration of plasma galectin-9 than that indicated by the GalPharma ELISA. This variation is due to aberrantly enhanced reactivity of the R&D Systems’ ELISA to degraded galectin-9 present in small quantities in the plasma. The GalPharma ELISA could detect only intact galectin-9 and its results correlated well with the plasma galectin-9 level obtained by western blotting. Conclusion: ELISA kits from R&D Systems reacts aberrantly higher against degraded galectin-9 than the intact galectin-9. Therefore, the existence of a small amount of degraded galectin-9 in a test sample hinders the quantification. As galectin-9 is a fragile protein, this is a serious concern when using this kit. Based on quantifications from the GalPharma ELISA, the median (25th-75th percentiles) galectin-9 concentration in healthy subjects in the current study cohort was calculated as 110 pg/mL (67 -154 pg/mL).

Abstract Background Neuroendocrine cell carcinoma is a rare variant of esophageal carcinoma. The characteristic clinical features and diagnosis of superficial neuroendocrine cell carcinoma remain to be established. We report a rare case of superficial coexistence of neuroendocrine cell carcinoma with squamous cell carcinoma treated by endoscopic submucosal dissection, and regional lymph node metastasis was detected after additional surgical treatment. Case presentation A 77-year-old Japanese man with esophageal squamous cell carcinoma received endoscopic submucosal dissection in en-bloc resection. Histopathological findings showed that lymphovascular invasion by the neuroendocrine cell carcinoma component occurred in the deep part of the muscularis mucosa. Regional lymph node metastasis was identified after additional surgical treatment. After surgical treatment, our patient received chemotherapy consisting of etoposide and carboplatin for 3 months. He is alive and shows no sign of disease recurrence 12 months after surgery. Conclusions This case report highlights the fact that even if neuroendocrine cell carcinoma is small and limited to superficial, the tumor has the potential for metastasis if lymphovascular invasion by the neuroendocrine cell carcinoma component occurs. In addition, this case indicates the necessity of close follow-up of small neuroendocrine cell carcinoma after treatment.

We aimed to examine the effects of a sodium glucose co-transporter 2 (SGLT2) inhibitor on systemic and intrarenal renin–angiotensin system (RAS) in subtotally nephrectomized non-diabetic rats, a model of chronic kidney disease (CKD). Oral administration of the selective SGLT2 inhibitor, TA-1887 (10 mg/kg/day), for 10 weeks induced glycosuria. However, plasma renin activity, plasma angiotensinogen levels, kidney angiotensin II contents and renal injury were not significantly affected by TA-1887. These data indicate that chronic treatment with an SGLT2 inhibitor does not activate the systemic and intrarenal RAS in subjects with non-diabetic CKD. Keywords: SGLT2 inhibitor, Renin–angiotensin system (RAS), Chronic kidney disease (CKD)

Abstract Background In patients with esophageal cancer, differentiation between lymph node metastasis and lymphadenopathies from sarcoidosis or sarcoid-like reactions of lymph nodes is clinically important. Herein, we report two esophageal cancer cases with lymph node involvement of sarcoid-like reaction or sarcoidosis. Case presentation One patient received chemotherapy and the other chemoradiotherapy as initial treatments. In both cases, [18F]-fluorodeoxyglucose positron emission tomography–computed tomography (FDG-PET/CT) was performed before and after chemo(radio)therapy. After the treatment, FDG uptake was not detected in the primary tumor, but it was slightly reduced in the hilar and mediastinal lymph nodes in both cases. These non-identical responses to chemo(radio)therapy suggest the presence of sarcoid-like reaction of lymph nodes associated with squamous cell carcinoma of the esophagus. Curative surgical resection was performed as treatment. Conclusions These FDG-PET/CT findings may be helpful to distinguish between metastasis and sarcoidosis-associated lymphadenopathy in esophageal cancer.

Esophagogastroduodenoscopy (EGD) has a high risk of virus transmission during the current coronavirus disease 2019 era, and preventive measures are under investigation. We investigated the effectiveness of a newly developed patient-covering negative-pressure box system (Endo barrier®) (EB) for EGD. Eighty consecutive unsedated patients who underwent screening EGD with EB use were prospectively enrolled. To examine the aerosol ratio before, during, and after EGD, 0.3- and 0.5-μm aerosols were measured every 60 s using an optical counter. Moreover, the degree of contamination of the examiners’ goggles and vinyl gowns was assessed before and after EGD using a rapid adenosine triphosphate (ATP) test for simulated droplets. Data were available in 73 patients and showed that 0.3- and 0.5-μm particles did not increase in 95.8% (70/73) and 94.5% (69/73) of patients during EGD under EB. There were no significant differences in the total 0.3- or 0.5-μm particle counts before versus after EGD. The difference in the ATP levels before and after EGD was −0.6 ± 16.6 relative light units (RLU) on goggles and 1.59 ± 19.9 RLU on gowns (both within the cutoff value). EB use during EGD may provide a certain preventive effect against aerosols and droplets, decreasing examiners’ exposure to viruses.

The kidney expresses protease-activated receptor-1 (PAR-1). PAR-1 is known as a thrombin receptor, but its role in kidney injury is not well understood. In this study, we examined the contribution of PAR-1 to kidney glomerular injury and the effects of its inhibition on development of nephropathy. Mice were divided into 3 groups: control, doxorubicin + vehicle (15 mg/kg doxorubicin and saline) and doxorubicin + Q94 (doxorubicin at 15 mg/kg and the PAR-1 antagonist Q94 at 5 mg/kg/d) groups. Where indicated, doxorubicin was administered intravenously and PAR-1 antagonist or saline vehicle by subcutaneous osmotic mini-pump. PAR-1 expression was increased in glomeruli of mice treated with doxorubicin. Q94 treatment significantly suppressed the increased albuminuria in these nephropathic mice. Pathological analysis showed that Q94 treatment significantly attenuated periodic acidâSchiff and desmin staining, indicators of podocyte injury, and also decreased glomerular levels of podocin and nephrin. Furthermore, thrombin increased intracellular calcium levels in podocytes. This increase was suppressed by Q94 and Rox4560, a transient receptor potential cation channel (TRPC)3/6 antagonist. In addition, both Q94 and Rox4560 suppressed the doxorubicin-induced increase in activities of caspase-9 and caspase-3 in podocytes. These data suggested that PAR-1 contributes to development of podocyte and glomerular injury and that PAR-1 antagonists have therapeutic potential. Keywords: Protease-activated receptor-1, Podocyte, Transient receptor potential cation channel, Kidney injury

Abstract Background Ten to forty percent of nonalcoholic steatohepatitis (NASH) and HCV-related chronic liver disease (CLD-C) patients have antinuclear antibodies (ANAs). However, the relationship between autoimmune response and insulin resistance remains uncertain among those patients. The primary purpose of this study was to investigate whether or not ANA status was associated with the development of insulin resistance and obesity in NASH and CLD-C patients. Methods Degrees of hepatic fibrosis and steatosis were evaluated by the classification proposed by Brunt et al. Obesity and insulin resistance were estimated by calculating body mass index and the value of homeostasis model of for assessment of insulin resistance (HOMA-IR), respectively. A revised scoring system was applied to the diagnosis of autoimmune hepatitis (AIH). Serum B-lymphocyte activating factor (BAFF) levels were determined, using an ELISA technique. Results Ten of 25 (40%) NASH patients and 9 of 22 (41%) CLD-C patients had ANAs, though the titers were weak in most patients. Only one NASH patient met the category of “definite” AIH among the enrolled patients. Serum IgG levels were significantly higher in NASH and CLD-C patients with ANAs than in those without ANAs, and NASH and CLD-C patients with ANAs had significantly higher HOMA-IR values than those without ANAs (6.81 ± 3.36 vs. 4.00 ± 2.57, p = 0.0305, 3.01 ± 1.31 vs. 1.28 ± 0.50, p = 0.0011). CLD-C patients with ANAs had more advanced hepatic fibrosis and steatosis than those without ANAs, while ANA status was not associated with hepatic fibrosis or steatosis in NASH patients. Obesity was independent of ANA status in both subjects. Serum BAFF levels were significantly higher in CLD-C patients with ANAs than those in CLD-C patients without ANAs (1303 ± 268 vs. 714 ± 143 pg/ml, p = 0.0036). A close correlation between serum BAFF level and the HOMA-IR value was observed in CLD-C patients (r = 0.467, p = 0.0485). Conclusion Our data suggest that NASH and CLD-C patients with ANAs have more severe insulin resistance than those without ANAs. More advanced insulin resistance deriving from excessive BAFF production may result in severe hepatic fibrosis and steatosis in CLD-C patients with ANAs.

The current standard for diagnosing cervical intraepithelial neoplasia (CIN) is colposcopy followed by punch biopsy. We have developed flexible magnifying endoscopy with narrow band imaging (ME-NBI) for the diagnosis of CIN. Here, we investigated the feasibility of targeted endoscopic forceps biopsy (E-Bx) under guidance of ME-NBI for the diagnosis of CIN. We prospectively enrolled 32 consecutive patients with confirmed or suspected high-grade CIN undergoing cervical conization. Next to colposcopy, the same patients underwent ME-NBI just before conization. ME-NBI was performed, and 30 E-Bx samples were taken from lesions suspicious for high-grade CIN and 15 from non-suspicious mucosa. We recalled 82 punch biopsy (P-Bx) specimens taken from lesions suspicious for high-grade CIN under colposcopic examination before enrollment. The proportion of sufficient biopsy samples, which had an entire mucosal layer with subepithelial tissue, for the diagnosis of CIN was evaluated by both methods. Performance of targeted E-Bx for the final diagnosis of at least high-grade CIN was calculated. Seventeen P-Bx specimens were unavailable. The proportion of sufficient samples with E-Bx was 84%, which was similar to that with P-Bx (87%) (p = 0.672). The sensitivity, specificity, and accuracy of ME-NBI using E-Bx was 92%, 81%, and 88%, respectively. In conclusion, ME-NBI-guided E-Bx samples were feasible for histological diagnoses of CIN, and further investigation of its diagnostic accuracy is warranted.

Diaphragmatic hernia (DH) is a defect, which can be congenital or can develop later in life. Moreover, chromosomal and genetic abnormalities, environmental exposures, and nutritional deficiencies may be related to the development of congenital DH. In contrast, the risk factors of acquired DH include traumas, such as blunt injuries due to traffic accidents and surgical procedures. We report the case of a 71-year-old man admitted to our gastroenterology department for the treatment of esophageal varices. Four days after the endoscopic treatment, the patient vomited severely and reported severe right upper abdominal pain. He was diagnosed with DH, and surgical fixation was performed. The diaphragmatic injury lesion was located on the estimated needle track of percutaneous radiofrequency ablation, which was performed through the thoracic diaphragm with artificial pleural effusion for hepatocellular carcinoma.

Endoscopic treatment can be a curative option for small carcinoid tumors with an extremely low risk of metastasis. Since most carcinoid tumors are characterized by a specific growth pattern in the submucosal (SM) layer, specialized endoscopic techniques for deeper resection to achieve clear vertical margins are needed. The endoscopic submucosal dissection (ESD) method in the SM space is superior to conventional endoscopic mucosal resection. However, the standard ESD technique sometimes fails to provide complete deep SM dissection due to insufficient SM lifting. Here, to resolve this problem, we describe our initial experience with an endoscopic SM tunneling technique that is effective for treating rectal carcinoid tumors.

Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) has emerged as a standard and convenient method for the sampling of subepithelial lesions (SELs). Immunohistological analysis is required to definitively distinguish mesenchymal tumors; however, EUS-FNA provides insufficient material to achieve this, especially for small SELs < 2 cm. We therefore previously reported a novel submucosal tunneling biopsy (STB) technique that utilizes endoscopic submucosal dissection (ESD) for sampling SELs. However, unresolved advanced technical issues have hindered its widespread application. Currently, a counter-traction technique is used to facilitate ESD. We here describe a technically simplified STB technique using clip-with-line traction for gastric SELs.

MicroRNAs (miRNAs) are short, endogenous RNAs that post-transcriptionally repress mRNAs. Over the course of evolution, many new miRNAs are known to have emerged and added to the existing miRNA repertoires of drosophilids and vertebrates. Despite the large number of miRNAs in existence, the complementary pairing of only ~7 bases between miRNAs and mRNAs is sufficient to induce repression. Thus, miRNA targeting is so widespread that genes coexpressed with a miRNA have evolved to avoid sites that are targeted by the miRNA. Besides this avoidance, little is known about the preferential modes of miRNA targeting. Therefore, to elucidate miRNA targeting preference and avoidance, we evaluated the bias of the number of miRNA targeting occurrences in relation to expression intensities of miRNAs and their coexpressed target mRNAs by surveying transcriptome data from human organs. We found that miRNAs preferentially target genes with intermediate levels of expression, while avoiding highly expressed ones, and that older miRNAs have greater targeting specificity, suggesting that specificity increases during the course of evolution.

Background. Endoscopic transpapillary gallbladder stenting (ETGBS) is an effective procedure for treating high-risk patients with acute cholecystitis and severe comorbidities. However, the efficacy of ETGBS for recurrent cholecystitis (RC) remains unclear. This study aimed to explore its efficacy in patients with RC for whom cholecystectomy is contraindicated because of its high surgical risk. Methods. Data on 19 high-risk patients who had undergone ETGBS for RC after initial conservative therapy in our institution between June 2006 and May 2012 were retrospectively examined. The primary outcome was the clinical success rate, which was defined as no recurrences of acute cholecystitis after ETGBS until death or the end of the follow-up period. Secondary outcomes were technical success rate and adverse events (AEs). Results. The clinical success rate of ETGBS was 100%, the technical success rate 94.7%, and AE rate 5%: one patient developed procedure-related mild acute pancreatitis. The clinical courses of all patients were as follows: four died of nonbiliary disease, and the remaining 15 were subsequently treated conservatively. The median duration of follow-up was 14.95 months (range 3–42 months). Conclusions. ETGBS is an effective alternative for managing RC in high-risk patients with severe comorbidities.

Background and study aims Endoscopic ultrasound-guided fine needle aspiration (FNA) for gastrointestinal subepithelial lesions (SELs) has limited diagnostic accuracy due to technical problems and small lesion size. We previously reported a novel submucosal tunneling biopsy (STB) technique for sampling SELs. This study aimed to evaluate the diagnostic ability and safety of STB compared to that of FNA for SELs. Patients and methods The study was a non-randomized, prospective comparative study with crossover design in patients with endoluminal gastric SELs. Forty-three patients, including 29 cases with lesions

High glucose has been demonstrated to induce angiotensinogen (AGT) synthesis in the renal proximal tubular cells (RPTCs) of rats, which may further activate the intrarenal renin-angiotensin system (RAS) and contribute to diabetic nephropathy. This study aimed to investigate the effects of high glucose on AGT in the RPTCs of human origin and identify the glucose-responsive transcriptional factor(s) that bind(s) to the DNA sequences of AGT promoter in human RPTCs. Human kidney (HK)-2 cells were treated with normal glucose (5.5 mM) and high glucose (15.0 mM), respectively. Levels of AGT mRNA and AGT secretion of HK-2 cells were measured by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Consecutive 5'-end deletion mutant constructs and different site-directed mutagenesis products of human AGT promoter sequences were respectively transfected into HK-2 cells, followed by AGT promoter activity measurement through dual luciferase assay. High glucose significantly augmented the levels of AGT mRNA and AGT secretion of HK-2 cells, compared with normal glucose treatment. High glucose also significantly augmented AGT promoter activity in HK-2 cells transfected with the constructs of human AGT promoter sequences, compared with normal glucose treatment. Hepatocyte nuclear factor (HNF)-5 was found to be one of the glucose-responsive transcriptional factors of AGT in human RPTCs, since the mutation of its binding sites within AGT promoter sequences abolished the above effects of high glucose on AGT promoter activity as well as levels of AGT mRNA and its secretion. The present study has demonstrated, for the first time, that high glucose augments AGT in human RPTCs through HNF-5, which provides a potential therapeutic target for diabetic nephropathy.

A growing body of evidence suggests that podocyte apoptosis is a major cause of decreased podocyte number, which leads to albuminuria and glomerular injury. The aim of this study was to clarify the molecular mechanisms of angiotensin II (Ang II)-induced apoptosis in cultured mouse podocytes. We examined the effects of Ang II (100 nmol/L) on apoptosis, superoxide anions, and cytosol pH in podocytes. For intracellular pH measurements, image analysis was conducted using confocal laser microscopy after incubation with carboxyseminaphthorhodafluor-1. Superoxide anions and intracellular pH were elevated with Ang II treatment. Apoptotic cell numbers, as measured by TUNEL staining and caspase 3 activity, were also augmented in the Ang II–treated group. Pre-treatment with olmesartan (100 nmol/L, an Ang II type 1–receptor blocker), apocynin (50 μmol/L, NADPH oxidase inhibitor), or 5-N,N hexamethylene amiloride [30 μmol/L, Na+/H+ exchanger type 1 (NHE-1) inhibitor] abolished Ang II–induced podocyte apoptosis, whereas NHE-1 mRNA and protein expression was not affected by Ang II treatment. Moreover, Ang II increased NHE-1 phosphorylation. These results suggest that superoxide production, NHE-1 activation, and intracellular alkalization were early features prior to apoptosis in Ang II–treated mouse podocytes, and may offer new insights into the mechanisms responsible for Ang II–induced podocyte injury. Keywords:: angiotensin II, Na+/H+ exchanger type 1 (NHE-1), intracellular pH, apoptosis, podocyte

We examined the effects of angiotensin II AT1–receptor blockade with olmesartan on high fat (HF) diet–induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet–fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats. NS + HF diet–fed DSS rats also showed higher plasma levels of thiobarbituric acid–reactive substances, aortic superoxide production, and mRNA levels of p22phox and gp91phox in aortic tissues than NS diet–fed DSS rats. Furthermore, acetylcholine-induced vasorelaxation of aorta from NS + HF diet–fed DSS rats was significantly reduced. In NS + HF diet–fed DSS rats, treatment with olmesartan medoxomil (10 mg/kg per day, p.o.) and hydralazine (25 mg/kg per day, p.o.) similarly decreased blood pressure. However, in these animals, only olmesartan normalized plasma levels of thiobarbituric acid–reactive substances, vascular superoxide in aortic tissues, and acetylcholine-induced vasorelaxation. These data indicate that HF diet–induced hypertension is associated with vascular oxidative stress and endothelial dysfunction in NS diet–treated DSS rats. Inhibition of angiotensin II AT1 receptors may elicit beneficial effects on HF-induced hypertension and vascular injury in subjects that have genetically enhanced sodium-sensitive blood pressure. Keywords:: high fat (HF) diet, Dahl salt-sensitive (DSS) rat, oxidative stress, endothelial dysfunction, angiotensin II (AngII)

Angiotensin II (Ang II) infusion into rats elevates local angiotensin II levels through an AT1 receptor–dependent pathway in the kidney. We examined whether treatment with an angiotensin-converting enzyme (ACE) inhibitor, temocapril, or an AT1-receptor blocker, olmesartan, prevented elevation of Ang II levels in the kidney of angiotensin I (Ang I)-infused rats. Rats were infused with Ang I (100 ng/min) and treated with temocapril (30 mg/kg per day, n = 10) or olmesartan (10 mg/kg per day, n = 9) for 4 weeks. Ang I infusion significantly elevated blood pressure compared with vehicle-infused rats (n = 6). Treatment with temocapril or olmesartan suppressed Ang I–induced hypertension. Temocapril suppressed both plasma and renal ACE activity. Ang I infusion increased Ang II content in the kidney. Interestingly, temocapril failed to reduce the level of Ang II in the kidney, while olmesartan markedly suppressed an increase in renal Ang II levels. These results suggest a limitation of temocapril and a benefit of olmesartan to inhibit the renal renin–angiotensin system and suggest the possible existence of an ACE inhibitor– insensitive pathway that increases Ang II levels in rat kidney. Keywords:: angiotensin-converting enzyme (ACE) inhibitor, angiotensin II, kidney

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren. Keywords:: aliskiren, valsartan, diabetic nephropathy

Mutations in the p53 gene leading to conformational changes in the p53 protein have been well established in many human cancers. Conformational changes and/or cellular accumulation of the protein may induce an immune response, resulting in circulating autoantibodies to p53, which have been documented in several types of cancers. Although rarely associated with autoimmune disease, a few reports have documented titres of anti-p53 autoantibodies in patients with autoimmune hepatitis and primary biliary cirrhosis. The clinical relevance of circulating autoantibodies to p53, therefore, remains unclear. Accordingly, this study aimed to examine the prevalence and clinical relevance of anti-p53 autoantibodies in patients with selected autoimmune liver diseases.

We recently demonstrated that cilnidipine, an L/N-type calcium channel blocker, elicits protective effects against glomerular podocyte injury, in particular, in obese hypertensive rats that express the N-type calcium channel (N-CC). Since the N-CC is known to be expressed in sympathetic nerve endings, we evaluated the reno-protective effects of cilnidipine in innervated and denervated spontaneously hypertensive rats (SHR). Male SHR were uninephrectomized and fed 4% high-salt diet (HS-UNX-SHR). Animals were divided into groups, as follows, and observed from 9 to 27 weeks of age: 1) vehicle (n = 14), 2) vehicle plus renal-denervation (n = 15), 3) cilnidipine (50 mg/kg per day, p.o.; n = 10), and 4) cilnidipine plus renal-denervation (n = 15). Renal denervation attenuated elevations in blood pressure, but failed to suppress urinary protein excretion and podocyte injury in HS-UNX-SHR. Cilnidipine in both innervated and denervated HS-UNX-SHR similarly induced significant antihypertensive effects, as well as suppressing the urinary protein excretion and podocyte injury, compared to vehicle-treated HS-UNX-SHR. These data indicate that renal nerves have a limited contribution to the cilnidipine-induced reno-protective effects in HS-UNX-SHR. Keywords:: cilnidipine, hypertension, N-type calcium channel, podocyte, renal sympathetic nerve