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Yuya Seko,1 Taichiro Nishikawa,1 Atsushi Umemura,1 Kanji Yamaguchi,1 Michihisa Moriguchi,1 Kohichiroh Yasui,1 Mayumi Kimura,2 Hiroaki Iijima,3 Toshio Hashimoto,3 Yoshio Sumida,4 Takeshi Okanoue,5 Yoshito Itoh1 1Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Osaka, Japan; 3Ikuyaku. Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan; 4Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan; 5Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan Aim: Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), is known to be associated with type 2 diabetes mellitus (T2DM) in high rate. The improvement in hepatic function due to sodium-glucose co-transporter 2 (SGLT2) inhibitors has been reported in T2DM patients with and without NAFLD. However, only a few studies have attempted to evaluate the role of SGLT2 inhibitors in T2DM patients with biopsy-proven NASH, and no detailed prospective studies including the individual hepatic fibrosis stage have been reported. Therefore, we investigated the effect of canagliflozin on hepatic function in T2DM patients with biopsy-confirmed NASH. Methods: T2DM patients with NASH (hepatic fibrosis stage 1–3 confirmed via liver biopsy, n=10) were enrolled and received canagliflozin (100 mg) once a day for 12 weeks. The primary end point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Secondary end points were liver function/fibrosis markers, metabolic parameters, and safety. Results: The change in ALT from baseline to week 12 was -23.9 U/L (95% CI –48.1 to 0.3, P=0.0526). Significant improvements in several hepatic function/fibrosis markers, such as aspartate aminotransferase, fibrosis-4 index, and FM-fibro index, and metabolic parameters including hemoglobin A1c and body weight were found. No serious or liver-related adverse events were reported. Regarding individual patients, different trends in ALT-lowering effects between stage 1 and stage 2/3 subjects were observed; the degree of ALT-lowering effect tended to be greater in the stage 1 group than in the stage 2/3 group. Conclusion: Our results suggest that canagliflozin is effective and well-tolerated in patients with T2DM and NASH. Canagliflozin may be useful for the treatment of T2DM patients with NASH, especially those in early stages of NASH. Keywords: canagliflozin, Japanese, NASH, fibrosis stages, SGLT2 inhibitor, type 2 diabetes mellitus

Background: There are many reports on the choice of treatment for and prognosis of left-sided obstructive colorectal cancer; however, few studies have focused on the prognostic factors of left-sided obstructive colorectal cancer. Therefore, we analyzed the prognostic factors using a post hoc analysis of a retrospective multicenter study in Japan. Methods: A total of 301 patients were enrolled in this study to investigate the prognostic factors for relapse-free survival. The relationships between sex, age, decompression for bridge to surgery, depth of invasion, lymph node metastasis, postoperative complications, adjuvant chemotherapy, carcinoembryonic antigen, carbohydrate antigen 19-9, neutrophil-to-lymphocyte ratio, and relapse-free survival were examined. Results: No change in the decompression method, T3 cancer, negative postoperative complications (grades 0–1 of Clavien-Dindo classification), and adjuvant chemotherapy during Stage III indicated a significantly better prognosis in a Cox univariate analysis. Lymph node metastasis was not selected as a prognostic factor. Excluding patients with <12 harvested lymph nodes (possible stage migration), lymph node metastasis was determined as a prognostic factor. In a Cox multivariate analysis, change in the decompression method, depth of invasion, lymph node metastasis (excluding N0 cases with <12 harvested lymph nodes), and adjuvant chemotherapy were prognostic factors. Conclusions: Similar to those in nonobstructive colorectal cancer, depth of invasion and lymph node metastasis were prognostic factors in left-sided obstructive colorectal cancer, and patients with <12 dissected lymph nodes experienced stage migration. Stage migration may result in disadvantages, such as not being able to receive adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is now the most common liver disease affecting high proportion of the population worldwide. NAFLD encompasses a large spectrum of conditions ranging from fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and cancer. NAFLD is considered as a multifactorial disease in relation to the pathogenic mechanisms. Oxidative stress has been implicated in the pathogenesis of NAFLD and NASH and the involvement of reactive oxygen species (ROS) has been suggested. Many studies show the association between the levels of lipid oxidation products and disease state. However, often neither oxidative stress nor ROS has been characterized, despite oxidative stress is mediated by multiple active species by different mechanisms and the same lipid oxidation products are produced by different active species. Further, the effects of various antioxidants have been assessed in human and animal studies, but the effects of drugs are determined by the type of active species, suggesting the importance of characterizing the active species involved. This review article is focused on the role of free radicals and free radical-mediated lipid peroxidation in the pathogenesis of NAFLD and NASH, taking characteristic features of free radical-mediated oxidation into consideration. The detailed analysis of lipid oxidation products shows the involvement of free radicals in the pathogenesis of NAFLD and NASH. Potential beneficial effects of antioxidants such as vitamin E are discussed. [ABSTRACT FROM AUTHOR]

An attenuated strain of Japanese yam mosaic virus (JYMV), designated T-3, was evaluated for its cross-protection efficacy against virulent (native) strains of JYMV in Chinese yam ( Dioscorea opposita) grown in farmers’ fields in Japan. Native strains of JYMV were detected by a polymerase chain reaction-based assay in all the Chinese yam plants grown from virus-free tubers in the first growing season in the fields. In contrast, the virus was detected in only one of fifty plants grown from tubers preinoculated with T-3 during the experiments for 6 years, suggesting that T-3 consistently cross-protected against native JYMV in Chinese yam in the field. Chinese yam plants preinoculated with T-3 produced significantly greater yield of tubers per plant compared with non-inoculated plants. [ABSTRACT FROM AUTHOR]

Rationale: Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury.Objectives: We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis.Methods: The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis.Measurements and Main Results: Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells.Conclusions: These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis. [ABSTRACT FROM AUTHOR]

Background: Impairment of gastric emptying is well recognized in patients with diabetes mellitus (DM), especially long-standing insulin-dependent diabetes mellitus (IDDM). The aim of this study was to evaluate the cause of delayed gastric emptying in DM patients.Methods: In 16 controls, 16 non-insulin-dependent diabetes mellitus (NIDDM) patients and 23 IDDM patients, gastric emptying was studied using the (13)C octanoic acid breath test. Breath samples were taken before a test meal labeled with 100 mg of (13)C octanoic acid, and at 15-min intervals over a 300-min period postprandially.Results: In all DM patients, the gastric emptying coefficient was lower than that in the controls (P < 0.05), and lag time and half-emptying time were significantly longer (P < 0.05). Both NIDDM and IDDM patients showed delayed (13)CO(2) excretion compared with the controls, but IDDM patients showed more delayed gastric emptying than NIDDM patients (P < 0.05). There were no significant differences in sex, HbA1c level, or the rate of neuropathy between the two groups.Conclusions: IDDM patients showed delayed gastric emptying compared with NIDDM patients, and the (13)C octanoic acid breath test is useful for evaluating DM patients with delayed gastric emptying. [ABSTRACT FROM AUTHOR]

Hypoxic–ischemic reperfusion injury causes either necrosis or apoptosis, and the influx of ionized calcium into cells is the major cause of both types of cell death. The aim of this study was to investigate whether or not the serum ionized calcium concentration in neonates with hypoxic–ischemic encephalopathy (HIE) could be used to predict their outcome.Serum samples were obtained shortly after birth from 20 HIE neonates who had not urinated or received treatment with calcium. Serum ionized calcium concentrations were adjusted for pH using a correction formula. Twelve neonates without any disease were selected as a control. The results were compared between nine HIE neonates who made a full recovery, 11 who died or had neurologic deficits, and 12 normal neonates.Considered together, the two HIE groups had lower serum ionized calcium concentrations (1.05 ± 0.10 mmol/L) than the control group (1.22 ± 0.07 mmol/L;P < 0.0001). Moreover, serum ionized calcium concentrations in the group with the poor outcome (0.99 ± 0.07 mmol/L) were lower than those in the group that made a full recovery (1.13 ± 0.06 mmol/L;P = 0.0016).The serum ionized calcium concentrations shortly after birth were significantly lower in neonates with HIE who had a poor outcome. Low concentrations may reflect multiple organ damage, particularly involving the brain. [ABSTRACT FROM AUTHOR]

BACKGROUND: The relationship between patient prognosis and various tumor biological factors has been reported previously, and prognostic factors of tumor biology may improve predictions of prognosis after hepatectomy for hepatocellular carcinoma (HCC) and may contribute to a new staging classification. This study was designed to provide an immunohistochemical analysis of tumor biological factors in patients who underwent hepatectomy for HCC. METHODS: Factors analyzed included p53 overexpression, microvessel counts, proliferating cell nuclear antigen, and expression of nm23. We examined 81 HCCs from patients with chronic liver diseases. RESULTS: In patients who underwent chemoembolization before surgery, or those a who had confluent multinodular tumor, p53 expression tended to be higher than in patients without chemoembolization (33% vs 11%) or those with a simple nodular tumor (28% vs 10%), but the difference was not statistically significant ( P = 0.051 and P = 0.092, respectively). A lower tumor microvessel count and negative nm23 expression were significantly associated with poor disease-free survival by univariate analysis ( P < 0.01 and P < 0.05, respectively). A lower tumor microvessel count was found to be a significant prognostic factor for disease-free and overall survivals (risk ratios, 2.44 and 3.13, respectively; P << 0.05), in addition to tumor size, vascular invasion, and longterm ascites, by Cox's multivariate analysis. CONCLUSIONS: Tumor microvessel count appears to be a useful prognostic marker for predicting HCC recurrence and patient survival. [ABSTRACT FROM AUTHOR]

Objective: To investigate the usefulness of the homeostasis model assessment as an index of insulin resistance (HOMA-IR) for evaluating the clinical course of patients with type 2 diabetes.Research Design and Methods: The usefulness of HOMA-IR and its relationship with insulin resistance assessed by the hyperinsulinemic-euglycemic clamp study (clamp IR) were evaluated in 55 Japanese patients with type 2 diabetes before and after treatment. The patients were subjected to diet (approximately 1,440-1,720 kcal/day) and exercise therapy (walking 10,000 steps daily) for 6 weeks during their hospitalization.Results: Univariate regression analysis disclosed a significant correlation between log-transformed HOMA-IR and log-transformed clamp IR before (r = -0.613, P < 0.0001) and after ( = -0.734, P < 0.0001) treatment. Neither the slopes (-0.71 +/- 0.12 vs. -0.79 +/- 0.09, F = 0.25, P = 0.61) nor the intercepts (y-intercept = 1.67 vs. 1.70, x-intercept = 2.36 vs. 2.15, F = 0.02, P = 0.88) of the regression lines between HOMA-IR and clamp IR were significantly different before and after treatment. There was a significant correlation between the decrease in log-transformed HOMA-IR and the increase in clamp IR during treatment (r = -0.617, P < 0.0001).Conclusions: HOMA-IR may constitute a useful method not only for diagnosing insulin resistance, but also for follow-up during the treatment of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The role of α-melanocyte stimulating hormone (MSH) in obesity has been well-documented. However, circulating α-MSH concentrations in obese men and their relationship with clinical indicators of obesity and glucose metabolism have not as yet been evaluated. METHODS: We measured the plasma concentrations of α-MSH in 15 obese and 15 non-obese male subjects. The relationship of the plasma concentrations of α-MSH with body mass index (BMI), body fat mass (measured by bioelectric impedance), body fat distribution (measured by computed tomography), insulin levels, insulin resistance (assessed by the glucose infusion rate (GIR) during an euglycemic hyperinsulinemic clamp study) and with the serum concentrations of leptin and TNF-α were also evaluated. RESULTS: In obese men, the plasma α-MSH concentrations were significantly increased compared with those in non-obese men (P<0.02). The plasma levels of α-MSH were positively correlated with BMI (r=0.560, P<0.05), fasting insulin levels (r=0.528, P<0.05) and with visceral fat area (r=0.716, P<0.01), but negatively correlated with GIR (r=-0.625, P<0.02) in obese male subjects. There were significant correlations between plasma concentrations of α-MSH and visceral fat area (r=0.631, P<0.02), and GIR (r=-0.549, P<0.05) in non-obese male subjects. Circulating concentrations of α-MSH were not significantly correlated with the serum concentrations of leptin and TNF-α in both obese and non-obese men. CONCLUSION: Circulating concentrations of α-MSH are significantly increased and correlated with insulin resistance in obese men. International Journal of Obesity (2000) 24, 1260–1264 [ABSTRACT FROM AUTHOR]

To clarify the relationship between multidrug resistance protein (MRP) and clinicopathologic features, the influence of adjuvant chemotherapy, and prognosis of patients who underwent resection of metastatic liver carcinomas originating from colorectal carcinomas, we examined the expression of MRP in tumor tissues by immunostaining. Specimens of 38 primary colorectal tumors and 44 metastatic liver tumors of colorectal origin were examined (metastatic group). We also examined 28 nonmetastatic colorectal carcinomas. The percentages of nonmetastatic tumors and of primary and metastatic tumors of the metastasis group that expressed MRP were similar. MRP expression in primary and metastatic tumors did not correlate with any clinicopathologic features. The use of adjuvant chemotherapy after operation for primary colorectal carcinomas was associated with increased MRP expression among metastatic liver tumors. Expression of MRP in the tumor did not influence the prognosis or survival rate after resection of primary or metastatic tumors. Our data suggest that MRP expression in metachronous liver metastases from colorectal carcinomas may be induced by administration of anticancer drugs but is not associated with clinicopathologic features of the tumor, liver metastasis, or prognosis. [ABSTRACT FROM AUTHOR]

A 54-year-old man, who had no clinical symptoms, underwent a routine health checkup at our hospital. Abdominal ultrasonography disclosed a well demarcated tumor containing a solid portion occupying the dilated left hepatic duct and a cystic portion expanding into the parenchyma of the left hepatic lobe, with mild dilatation of the intrahepatic bile ducts. These findings were later confirmed by computed tomography (CT) and magnetic resonance imaging. Endoscopic retrograde cholangiography revealed a complete defect at the level of the left hepatic duct, while drip infusion cholangiographic-CT (DIC-CT) disclosed a defect of the left hepatic duct only, with the distal portions of the left intrahepatic ducts being visualized on the image. Hepatic angiography revealed light stains in the solid portion in the parenchymal phase. At left lobectomy, a multiloculated polyp-like tumor was found arising from the left hepatic duct and expanding into the parenchyma of the left hepatic lobe. Microscopically, all the lining cells in the cysts and the tumor cells in the solid portion showed the features of papillary adenocarcinoma. In this patient with extrahepatic biliary cystadenocarcinoma, DIC-CT was useful in identifying the site of origin of the tumor, and hepatic angiography was also useful in differentiating this rare malignant tumor from benign cystadenoma. [ABSTRACT FROM AUTHOR]

SummaryAim To determine the relationship of the polymorphism at codon 54 of the intestinal fatty acid binding protein gene (FABP2) with insulin resistance and susceptibility to Type 2 diabetes mellitus (DM) in the Japanese population. Methods We evaluated the polymorphism by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 150 Type 2 DM patients and 147 healthy control subjects. The frequency of alleles encoding threonine (Thr54) and alanine (Ala54) at codon 54 of FABP2 in Type 2 DM patients was compared with that of healthy controls. Insulin sensitivity was assessed by the hyperinsulinaemic euglycaemic clamp in Type 2 DM patients with Ala54 homozygotes, Ala54/Thr54 heterozygotes and Thr54 homozygotes and by homeostasis model assessment (HOMA) in the nondiabetic group. Results The frequency of alleles encoding Ala54 and Thr54 was 0.59 and 0.41 in Type 2 DM patients, respectively, similar to that observed in nondiabetic controls (0.64 for Ala54 and 0.36 for Thr54). Insulin sensitivity was not significantly different between subjects with and without Thr54 allele either within the DM group or healthy controls. Conclusions The allele encoding threonine in the FABP2 does not predispose to Type 2 DM or insulin resistance in the Japanese population Diabet. Med. 16, 119–124 (1999). [ABSTRACT FROM AUTHOR]