[A case of repeated severe hypoglycemia caused by accidental ingestion of sulfonylurea in an elderly patient].

An 81-year-old man was being treated with oral medication for chronic heart failure and epilepsy. He had no history of diabetes, cirrhosis, or gastric surgery. He was admitted to our hospital due to disturbance of consciousness. His blood glucose level was 6 mg/dl, with a relatively high insulin level (14.4 µU/ml). Computed tomography and a 48 h fasting test showed no signs of insulinoma. There were no signs of reactive hypoglycemia, insulin autoimmune syndrome, or adrenal insufficiency. His wife had been taking medication for diabetes, including sulfonylurea. She had dementia, and he managed her medication. Since his medication was found in his wife's medicine box, we considered the possibility that he might have taken sulfonylurea by mistake. We asked his daughter to manage their medicine. However, one month later, he was admitted to our hospital again with severe hypoglycemia. His wife's HbA1c value and estimated glomerular filtration rate were 6.9% and 30 ml/min/1.73 m2. We asked his wife's home doctor to stop sulfonylurea prescription, and the hypoglycemia did not recur, with his wife's level of HbA1c remaining stable.Elderly individuals and patients with an impaired renal function are prone to hypoglycemia from sulfonylurea. In elderly households, there is a possibility of accidental ingestion of oral hypoglycemic agents by other family members living with the patient. It is therefore necessary to understand and manage the medications of family members living together. It is also important to avoid prescribing medications with a high risk of hypoglycemia to elderly patients.

Porphyromonas gingivalis impairs glucose uptake in skeletal muscle associated with altering gut microbiota.

Skeletal muscles have a high metabolic capacity, which play key roles in glucose metabolism. Although periodontal disease increases the risk of metabolic syndrome, the relationship between periodontal bacterial infection and skeletal muscle metabolic dysfunction is unclear. We found that anti-Porphyromonas gingivalis (Pg) antibody titers positively correlated with intramuscular adipose tissue content (IMAC), fasting blood glucose, and HOMA-IR in metabolic syndrome patients. In C57BL/6J mice fed a high-fat diet, recipients of oral Pg (HFPg) had impaired glucose tolerance, insulin resistance, and higher IMAC compared to recipients of saline (HFco). The soleus muscle in HFPg mice exhibited fat infiltration and lower glucose uptake with higher Tnfa expression and lower insulin signaling than in HFco mice. Gene set enrichment analysis showed that TNFα signaling via NFκB gene set was enriched in the soleus muscle of HFPg mice. Moreover, TNF-α also decreased glucose uptake in C2C12 myoblast cells in vitro. Based on 16S rRNA sequencing, Pg administration altered the gut microbiome, particularly by decreasing the abundance of genus Turicibacter. Microbial network of the gut microbiome was dramatically changed by Pg administration. Our findings suggest that infection with Pg is a risk factor for metabolic syndrome and skeletal muscle metabolic dysfunction via gut microbiome alteration.

MAFLD better predicts the progression of atherosclerotic cardiovascular risk than NAFLD: Generalized estimating equation approach.

AIM: Metabolic associated fatty liver disease (MAFLD) partly overlaps with non-alcoholic fatty liver disease (NAFLD). Thus, using a generalized estimating equation (GEE) approach, we aimed to investigate the difference in worsening of atherosclerotic cardiovascular disease (ASCVD) risk between patients with MAFLD and NAFLD. We also investigated factors related to the difference between the two groups. METHODS: We enrolled 2306 subjects with fatty liver (MAFLD 80.7%, NAFLD 63.4%). Subjects with MAFLD/NAFLD were sub-classified into three groups: NAFLD with no metabolic dysfunction (non-Met NAFLD), overlapping, and MAFLD with moderate alcohol consumption (mod-Alc MAFLD). ASCVD risk was estimated by non-invasive tests, including the Suita score. An event was defined as worsening of these scores from the low-risk to the high-risk group. Independent factors for the event were analyzed by Cox regression analysis with the GEE. RESULTS: In Cox regression analysis, MAFLD (HR 1.08, 95% CI 1.02-1.15, p = 0.014) and alcohol consumption (20-39 g/day; HR 1.73, 95% CI 1.26-2.36, p = 0.001) were independently associated with worsening of the Suita score. In a subanalysis, the incidence of the event was significantly lower in non-Met NAFLD than in the overlapping group (HR 0.70, 95% CI 0.50-0.98, p = 0.042). However, no significant difference was observed in the incidence between the overlapping and mod-Alc MAFLD group (HR 1.19, 95% CI 0.89-1.58, p = 0.235). CONCLUSIONS: The GEE approach demonstrates that MAFLD better identifies patients with worsening of ASCVD risk than NAFLD. Moreover, the superiority of MAFLD over NAFLD was due to the presence of metabolic dysfunction rather than moderate alcohol consumption.

Severity of constipation related to palonosetron during first-line chemotherapy: a retrospective observational study.

PURPOSE: Palonosetron, a long-acting 5-HT3 receptor antagonist, is an effective antiemetic agent for chemotherapy-induced nausea and vomiting; however, it sometimes causes severe constipation. The aim of the present study was to evaluate the severity of palonosetron-related constipation. METHODS: We retrospectively analyzed the incidence and severity of constipation after intravenous administration of 0.75-mg palonosetron in 150 chemotherapy-naïve patients who received first-line chemotherapy at Saga University Hospital. Constipation was classified into grades 1-5 according to the Common Terminology Criteria for Adverse Events version 5.0. Multiple logistic regression analysis was performed to identify factors associated with palonosetron-related worsening of constipation to grade 2 or higher. RESULTS: Palonosetron significantly increased the incidence and severity of constipation (incidence: before vs. after palonosetron, 35.4% vs. 74.0%, p < 0.0001, and severity: before vs. after palonosetron, 26.7% and 8.7% in grades 1 and 2, respectively, vs. 46.7%, 23.3%, and 4.0% in grades 1, 2, and 3, respectively, p < 0.0001). Despite the use of laxatives, 4.0% of patients had grade 3 constipation requiring manual evacuation. Combination treatment with aprepitant (odds ratio (OR), 10.9; 95% confidence interval (CI), 1.3-90.0; p = 0.026) and older age (OR, 1.25; 95% CI, 1.01-1.57; p = 0.039) were factors associated with the severity of constipation. CONCLUSION: Constipation was more severe in patients receiving combination treatment with aprepitant than in those treated with palonosetron alone. Older age was also associated with increased risk of severe palonosetron-related constipation. Identification of risk factors can help target risk-based laxative therapy.

Lifestyle- and Comorbidity-Related Risk Factors Associated with Prescription of Gastric Acid Secretion Inhibitors to Japanese Patients Who Were Helicobacter pylori Negative and Had No Upper Gastrointestinal Lesions.

OBJECTIVE: The aim of this study was to determine the characteristics of patients without Helicobacter pylori infection who were prescribed antacid medications (potassium-competitive acid blockers, proton pump inhibitors, and/or H2 receptor antagonist) and had no upper gastrointestinal lesions detected by endoscopy. METHODS: This cross-sectional study included the patients who underwent upper gastrointestinal endoscopy in our institution between August 2017 and July 2018. They were aged from 55 to 89 years, had no upper gastrointestinal lesions detected by endoscopy, and no H. pylori infection. Exclusion criteria comprised low-dose aspirin and/or nonsteroidal anti-inflammatory drugs. The subjects were allocated to middle-aged (55-69 years) and older age groups (70-89 years). The relationships between antacid medications and patient lifestyle and comorbidities were evaluated by multivariate analyses. RESULTS: Of the 420 patients, 272 were in the middle-aged group and 148 patients in the older age group. Age was found to be a risk factor for antacid medications in both groups (p = 0.002, p = 0.007). No other lifestyle related factors were risk factors. As to comorbidities, hiatal hernia was positively associated with antacid medications in the middle-aged group (p = 0.002). Hypertension and Ca-blockers were positively associated with prescription of antacids in the older age group (p = 0.013); this association was not significant in the middle-aged group. CONCLUSIONS: Three lifestyle-related and/or comorbidity-associated factors known to exacerbate gastroesophageal reflux, namely, age, hiatus hernia, and Ca-blockers, were associated with prescription of antacid medications, even in patients without endoscopic reflux esophagitis.

Decline incidence in upper gastrointestinal bleeding in several recent years: data of the Japan claims database of 13 million accumulated patients.

This study was to examine the recent trends in upper gastrointestinal bleeding in Japan using a large-scale real-world database. The incidence of upper gastrointestinal bleeding was evaluated in the Japan Medical Data Center claims database of 13,019,713 patients aged 20 to 74 years with traceability for 3 months from 2009 to 2014. The incidence was compared with peptic ulcers and gastroesophageal reflux disease. The prescription of medications was also evaluated. The incidence of bleeding was 0.137%, 0.121%, 0.113%, 0.106%, 0.099%, and 0.105% during 2009 to 2014 with a time-dependent decline (p<0.001). Peptic ulcers (>10 times higher than the incidence of bleeding) decreased with time (p<0.001), whereas gastroesophageal reflux disease increased (p = 0.006). Upper gastrointestinal bleeding was higher in male patients and older patients (60-74 years old) (p<0.001 respectively). The prescription rate of antithrombotic medications and proton pump inhibitors increased from 2009 to 2014 (p<0.001 respectively). The incidence of upper gastrointestinal bleeding decreased from 2009 to 2014 in this relatively large-scale real-world database in Japan, concomitant with the decrease in peptic ulcers. The decreased incidence might have been due to changes in the disease structure and therapeutic strategies over time.

Combined effect of canagliflozin and exercise training on high-fat diet-fed mice.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been reported to improve obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in addition to exercise training, whereas the combined effects remain to be elucidated fully. We investigated the effect of the combination of the SGLT2i canagliflozin (CAN) and exercise training in high-fat diet-induced obese mice. High-fat diet-fed mice were housed in normal cages (sedentary; Sed) or wheel cages (WCR) with or without CAN (0.03% of diet) for 4 wk. The effects on obesity, glucose metabolism, and hepatic steatosis were evaluated in four groups (Control/Sed, Control/WCR, CAN/Sed, and CAN/WCR). Numerically additive improvements were found in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and the fatty liver of the CAN/WCR group, whereas CAN increased food intake and reduced running distance. Exercise training alone, CAN alone, or both did not change the weight of skeletal muscle, but microarray analysis showed that each resulted in a characteristic change of gene expression in gastrocnemius muscle. In particular, in the CAN/WCR group, there was acceleration of the angiogenesis pathway and suppression of the adipogenesis pathway compared with the CAN/Sed group. In conclusion, the combination of an SGLT2i and exercise training improves obesity, insulin resistance, and NAFLD in an additive manner. Changes of gene expression in skeletal muscle may contribute, at least in part, to the improvement of obesity and insulin sensitivity.

Impaired upregulation of Stat2 gene restrictive to pancreatic ß-cells is responsible for virus-induced diabetes in DBA/2 mice.

Viral infection is a putative causal factor for the development of type 1 diabetes, but the exact pathogenic mechanism of virus-induced diabetes (VID) remains unclear. Here, to identify the critical factors that regulate VID, we analyzed encephalomyocarditis D (EMC-D) VID-sensitive DBA/2 mice in comparison with resistant B6 mice. EMC-D virus-induced cell death occurred more frequently in DBA/2 ß-cells than in B6 ß-cells with 100U/ml IFN-ß priming in vitro. We therefore purified ß-cells using flow cytometry from mice two days after EMC-D virus infection and subjected them to microarray analysis. As a results, innate immune response pathway was found to be enriched in B6 ß-cells. The signal transducer and activator of transcription 2 (Stat2) gene interacted with genes in the pathway. Stat2 gene expression levels were lower in DBA/2 mice than in B6 mice, restrictive to ß-cells. Moreover, administration of IFN-ß failed to upregulate Stat2 gene in DBA/2 ß-cells than in those of B6 in vivo. The viral titer significantly increased only in the DBA/2 pancreas. Thus, these provided data suggest that impaired upregulation of Stat2 gene restrictive to ß-cells at the early stage of infection is responsible for VID development in DBA/2 mice.

MAFLD identifies patients with significant hepatic fibrosis better than NAFLD.

BACKGROUND & AIMS: Diagnostic criteria for metabolic associated fatty liver disease (MAFLD) have been proposed, but not validated. We aimed to compare the diagnostic accuracy of the MAFLD definition vs the existing NAFLD criteria to identify patients with significant fibrosis and to characterize the impact of mild alcohol intake. METHODS: We enrolled 765 Japanese patients with fatty liver (median age 54 years). MAFLD and NAFLD were diagnosed in 79.6% and 70.7% of patients respectively. Significant fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥6.6 kPa using shear wave elastography. Mild alcohol intake was defined as <20 g/day. Factors associated with significant fibrosis were analysed by logistic regression and decision-tree analyses. RESULTS: Liver stiffness was higher in MAFLD compared to NAFLD (7.7 vs 6.8 kPa, P = .0010). In logistic regression, MAFLD (OR 4.401; 95% CI 2.144-10.629; P < .0001), alcohol intake (OR 1.761; 95% CI 1.081-2.853; P = .0234), and NAFLD (OR 1.721; 95%CI 1.009-2.951; P = .0463) were independently associated with significant fibrosis. By decision-tree analysis, MAFLD, but not NAFLD or alcohol consumption was the initial classifier for significant fibrosis. The sensitivity for detecting significant fibrosis was higher for MAFLD than NAFLD (93.9% vs 73.0%). In patients with MAFLD, even mild alcohol intake was associated with an increase in the prevalence of significant fibrosis (25.0% vs 15.5%; P = .0181). CONCLUSIONS: The MAFLD definition better identifies a group with fatty liver and significant fibrosis evaluated by non-invasive tests. Moreover, in patients with MAFLD, even mild alcohol consumption is associated with worsening of hepatic fibrosis measures.

Profiles of advanced hepatic fibrosis evaluated by FIB-4 index and shear wave elastography in health checkup examinees.

AIM: Advanced hepatic fibrosis is seen in individuals with potential hepatocellular carcinoma and cardiovascular disease. Hepatic fibrosis can be assessed using a combination of the FIB-4 index and imaging modalities, including shear wave elastography. We aimed to investigate the prevalence of advanced fibrosis in the general population and the profiles associated with advanced fibrosis using a data-mining analysis. METHODS: We enrolled 1155 health checkup examinees (median age 53 years, 685 women, 470 male). Advanced fibrosis was defined by FIB-4 index ≥1.3 and liver stiffness ≥8.07 kPa using shear wave elastography. Participants were classified as normal-mild fibrosis (n = 1035) or advanced fibrosis (n = 120). Factors associated with advanced fibrosis were analyzed by logistic regression and decision-tree analyses. RESULTS: Advanced fibrosis was observed in 10.4% of participants (120/1155). In the logistic regression analysis, independent factors for advanced fibrosis were age (≥75 years; OR 2.12, 95% CI 1.021-4.415; P = 0.0419) and the presence of metabolic syndrome (OR 2.51, 95% CI 1.416-4.462; P = 0.0017). The decision-tree analysis showed two profiles associated with advanced fibrosis: profile 1 - individuals aged ≥65 years with metabolic syndrome and mild-to-moderate alcohol consumption (prevalence of advanced fibrosis 73.3%); and profile 2 - individuals without metabolic syndrome, aged ≥75 years, with no exercise habit (prevalence of advanced fibrosis 56.3%). CONCLUSIONS: Advanced fibrosis was observed in 10.4% of health checkup examinees. Furthermore, we showed that aging, metabolic syndrome with mild-to-moderate alcohol consumption, and physical inactivity were associated with advanced fibrosis. Thus, prevention of metabolic syndrome and alcohol withdrawal, as well as exercise habits, might inhibit the progression of hepatic fibrosis.

Accuracy of the Enhanced Liver Fibrosis test, and combination of the Enhanced Liver Fibrosis and non-invasive tests for the diagnosis of advanced liver fibrosis in patients with non-alcoholic fatty liver disease.

AIM: The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non-alcoholic fatty liver disease. METHODS: ELF cut-off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy-confirmed non-alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224). RESULTS: The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut-off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut-off 10.83) and LSM (cut-off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis-4 index (cut-off 2.67) and ELF (cut-off 9.34) increased the sensitivity to 95.9%. CONCLUSIONS: ELF can identify advanced liver fibrosis in non-alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non-invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.

Diagnostic accuracy of FibroScan-AST score to identify non-alcoholic steatohepatitis with significant activity and fibrosis in Japanese patients with non-alcoholic fatty liver disease: Comparison between M and XL probes.

AIM: Recently, FibroScan-AST (FAST) score was reported to be effective for identifying non-alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut-off values and diagnostic accuracy between the FibroScan M and XL probes. METHODS: Eighty-two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut-off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut-off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut-off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe. CONCLUSIONS: There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.

Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis.

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive ß-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

Epidemiological survey of hemoglobin A1c and liver fibrosis in a general population with non-alcoholic fatty liver disease.

AIM: The association between glycemia and liver fibrosis was analyzed using hemoglobin A1c (HbA1c) and the Fibrosis-4 (FIB-4) index in a large general population cohort that underwent a health checkup. METHODS: A total of 6927 subjects without hepatitis B or C virus infection or habitual alcohol intake were enrolled. Non-alcoholic fatty liver disease (NAFLD) was diagnosed by ultrasonography and potential liver fibrosis (FIB-4 index ≥1.3) in NAFLD was analyzed in relation to HbA1c level. Factors associated with potential liver fibrosis of NAFLD were also analyzed. RESULTS: The overall frequency of NAFLD was 27.9% (1935 subjects) and the frequency of NAFLD by HbA1c level (<4.9%, 5.0-5.9%, 6.0-6.9%, 7.0-7.9%, ≥8.0%) was 16%, 27%, 54%, 53%, and 54%, respectively. Among the 1935 NAFLD cases, the frequency of potential liver fibrosis was 25.2% (487 subjects) overall and 19%, 22%, 30%, 52%, and 31%, respectively, by HbA1c category. From multivariate analysis, an HbA1c level ≥6.5% was significantly associated with potential liver fibrosis (P = 0.017, hazard ratio = 1.7). CONCLUSIONS: The prevalence of NAFLD and liver fibrosis of NAFLD increased according to glycemia, up to 8.0% HbA1c. Measuring HbA1c and calculating the FIB-4 index in health checkups could help to identify potential cases of liver fibrosis of NAFLD, which should then be further evaluated using other techniques to confirm liver fibrosis.

Correlation of Barrett's esophagus with colorectal polyps in Japanese patients: A retrospective chart review.

BACKGROUND AND AIM: Barrett's esophagus and colorectal polyps have several overlapping risk factors. Whereas several reports in Western countries have indicated a close relationship between Barrett's esophagus and colorectal polyps, the relationship between these two diseases remains unclear in Japan. This study was performed to determine whether the prevalence of Barrett's esophagus is related to that of colorectal polyps in Japanese patients. METHODS: The present retrospective chart review included 1582 Japanese patients who underwent both total colonoscopy and esophagogastroduodenoscopy from January 2010 to December 2016. The data on colorectal polyps and Barrett's esophagus were obtained from the endoscopic findings. The medical record of each patient was checked for age, sex, body mass index, smoking, alcohol drinking, use of acid suppression agents, and comorbidities including a history of diabetes, ischemic heart disease, gastroesophageal reflux disease, hiatal hernia, and Helicobacter pylori infection. RESULTS: Colorectal polyps were detected in 789 of the 1582 patients (49.9%). Barrett's esophagus was detected in 233 patients (14.7%), and most cases of Barrett's esophagus (n = 229) were classified as short-segment Barrett's esophagus. Colorectal polyps were more frequent in patients with than without Barrett's esophagus (odds ratio, 1.79; 95% confidence interval, 1.31-2.46; P < 0.001). In addition to Barrett's esophagus, the data indicated that old age, male sex, obesity, smoking, alcohol drinking, diabetes mellitus, and ischemic heart disease were independent risk factors for colorectal polyps. CONCLUSIONS: The present study revealed the correlation between the prevalence of Barrett's esophagus and colorectal polyps in Japanese patients.

Risk Factors for Delayed Hemorrhage after Colonic Endoscopic Mucosal Resection in Patients Not on Antithrombotic Therapy: Retrospective Analysis of 3,844 Polyps of 1,660 Patients.

BACKGROUND/AIMS: Colonic endoscopic mucosal resection (EMR) is safe for patients without antithrombotic therapy; however, EMR is associated with several risks. This study was performed to evaluate the risk of delayed hemorrhage in patients undergoing EMR without antithrombotic therapy. METHODS: In the present retrospective single-center study, 1,792 patients without antithrombotic therapy underwent colonic EMR from March 2012 to December 2016 at the Saga Medical Centre Koseikan. Risk factors were evaluated with respect to patient and lesion characteristics, the endoscopist's experience, and preventive hemoclips. Delayed hemorrhage was defined as bleeding for which emergency endoscopic hemostasis was applied >24 h after EMR. RESULTS: Among the 1,792 patients, 1,660 with 3,844 tumors were evaluated. Delayed hemorrhage occurred in 43 patients (2.6%) and 46 polyps (1.2%). Preventive hemoclips were applied in 996 patients (60.0%). Univariate analysis indicated that delayed hemorrhage occurred more frequently in young patients (3-39 years, p < 0.001, 40-59 years, p = 0.005) compared to > 60 years and in association with large polyps (> 10 mm, p = 0.003), hemoclip (p = 0.019), and pedunculated polyps (p = 0.024). Multivariate analysis indicated that risk factors for hemorrhage were young age (age of 3-39 years p < 0.001, 40-59 years, p = 0.005) and large polyps (> 10 mm, p < 0.001). The risk of delayed hemorrhage was increased by an estimated 8% with a 1-mm increase in polyp size. CONCLUSION: The present study suggests that young age (under 60 years old) and large polyp size are risk factors for causing delayed hemorrhage after colonic EMR in patients without antithrombotic therapy.

Shorter Relapse-Free Period after Leukocyte Removal Therapy in Younger than Older Patients with Ulcerative Colitis.

BACKGROUND: Leukocyte removal therapy (LRT) is an effective treatment for active ulcerative colitis (UC). The present study was performed to evaluate the relapse-free period after LRT and identify risk factors for relapse. METHODS: In total, 94 patients who underwent first-time LRT for remission of moderate to severe UC from April 2004 to March 2016 were enrolled in the present study. The patients were randomly assigned to one of 2 treatments: leukocytapheresis (LCAP; n = 43) or granulocyte and monocyte/macrophage adsorptive apheresis (GMA; n = 51). The 5-year cumulative relapse-free rate and risk factors for relapse were evaluated. RESULTS: The therapeutic response rate was 82% for GMA and 70% for LCAP without a statistically significant difference. The 5-year relapse-free rate was 34.7% in the LRT group. The 5-year relapse-free rate in patients aged > 40 years was 49.9%, which was significantly higher than that in patients aged ≤40 years (22.9%, p < 0.01). The relapse-free period was longer in the older than younger patients. CONCLUSIONS: The relapse-free period after LRT was examined in patients with UC, and 34.7% of patients achieved clinical remission within a 5-year period. The risk factor for early relapse after LRT was younger age.

Mechanisms of PKC-Mediated Enhancement of HIF-1α Activity and its Inhibition by Vitamin K2 in Hepatocellular Carcinoma Cells.

Hypoxia-inducible factor 1 (HIF-1) plays important roles in cancer cell biology. HIF-1α is reportedly activated by several factors, including protein kinase C (PKC), in addition to hypoxia. We investigated the role of PKC isoforms and the effects of vitamin K2 (VK2) in the activation process of HIF-1α. Human hepatocellular carcinoma (HCC)-derived Huh7 cells were cultured under normoxic and hypoxic (1% O2) conditions with or without the PKC stimulator TPA. The expression, transcriptional activity and nuclear translocation of HIF-1α were examined under treatment with PKC inhibitors, siRNAs against each PKC isoform and VK2. Hypoxia increased the expression and activity of HIF-1α. TPA increased the HIF-1α activity several times under both normoxic and hypoxic conditions. PKC-δ siRNA-mediated knockdown, PKC-δ inhibitor (rottlerin) and pan-PKC inhibitor (Ro-31-8425) suppressed the expression and transcriptional activity of HIF-1α. VK2 significantly inhibited the TPA-induced HIF-1α transcriptional activity and suppressed the expression and nuclear translocation of HIF-1α induced by TPA without altering the HIF-1α mRNA levels. These data indicate that PKC-δ enhances the HIF-1α transcriptional activity by increasing the nuclear translocation, and that VK2 might suppress the HIF-1α activation through the inhibition of PKC in HCC cells.

"Weariness" and "unpleasantness" reduce adherence to branched-chain amino acid granules among Japanese patients with liver cirrhosis: results of a single-center cross-sectional survey.

AIM: Branched-chain amino acids (BCAA) are valuable in the treatment of liver cirrhosis because they increase serum albumin levels. Poor adherence to BCAA may adversely affect prognosis, but little is known about factors predicting adherence. We undertook a survey of patients prescribed BCAA for the treatment of cirrhosis. METHODS: Pharmacists carried out face-to-face interviews with patients (or their representatives) prescribed any of nine BCAA formulations. Question categories included patient characteristics, prescription of BCAA granules, and perceptions of BCAA administration, including adherence and possible factors that might impact adherence. "Poor adherence" was defined as "not taking the medication appropriately" or "forgetting to take the medication". RESULTS: Overall, 253 patients (or representatives) completed the survey, of whom 135 were men, 114 were women, and 148 were ≥70 years old. Most patients (163) were prescribed BCAA for ≥2 years and were using three packs per day. Thirty-two patients did not take their medication appropriately and 69 sometimes forgot to administer it. Weariness of taking the medication (P < 0.001) and the perceived unpleasantness (P = 0.023) of the medication in terms of its taste and volume were significantly associated with poor adherence. The patients reported that the most influential educators were general practitioners, followed by certified hepatologists, then pharmacists. CONCLUSION: Most patients had good adherence to BCAA in clinical practice. Poor adherence was associated with weariness with taking medication, and the unpleasantness of the medication itself. Patient education from general practitioners and hepatologists combined with adherence counseling from pharmacists may help improve adherence.

Sarcopenia is a risk factor for the recurrence of hepatocellular carcinoma after curative treatment.

BACKGROUND AND AIM: Sarcopenia, initially proposed as decreased of muscle mass and strength, is associated with aging and malignant diseases. The aim of the present study was to determine whether there is a correlation between sarcopenia and the recurrence of hepatocellular carcinoma (HCC) after curative treatment. METHODS: We conducted a retrospective analysis of consecutive naive patients with HCC who underwent curative resection or radiofrequency ablation. To eliminate the influence of cause or the severity of liver damage, subjects were limited to those with HCC with hepatitis C-related cirrhosis and Child-Pugh class A liver function. Patients were assessed using computed tomographic measurement of muscle mass at the level of the third lumbar (L3) vertebrae, the L3 skeletal muscle index (L3 SMI). Sarcopenia was defined by using previously published, sex-specific cut-off value. RESULTS: Sarcopenia was present in 61 of 92 patients. Patients' median age was 71.5 years (range, 47-84), and the baseline characteristics of patients were comparable between patients with and without sarcopenia except for sex, serum albumin level, prothrombin time, diabetes mellitus and body mass index. Recurrence rates at 1, 3 and 5 years were 39.1%,77.1%,81.7% for patients with sarcopenia and 23.5%,59.5% and 75.7% for patients without sarcopenia, respectively (P = 0.03). Multivariate Cox analysis revealed that sarcopenia and preoperative α-fetoprotein of more than 40 ng/mL were significant independent factors for recurrence. CONCLUSION: Sarcopenia is a risk factor for recurrence in patients with HCC who were treated with curative treatment.