Brown adipose tissue dysfunction promotes heart failure via a trimethylamine N-oxide-dependent mechanism.

Low body temperature predicts a poor outcome in patients with heart failure, but the underlying pathological mechanisms and implications are largely unknown. Brown adipose tissue (BAT) was initially characterised as a thermogenic organ, and recent studies have suggested it plays a crucial role in maintaining systemic metabolic health. While these reports suggest a potential link between BAT and heart failure, the potential role of BAT dysfunction in heart failure has not been investigated. Here, we demonstrate that alteration of BAT function contributes to development of heart failure through disorientation in choline metabolism. Thoracic aortic constriction (TAC) or myocardial infarction (MI) reduced the thermogenic capacity of BAT in mice, leading to significant reduction of body temperature with cold exposure. BAT became hypoxic with TAC or MI, and hypoxic stress induced apoptosis of brown adipocytes. Enhancement of BAT function improved thermogenesis and cardiac function in TAC mice. Conversely, systolic function was impaired in a mouse model of genetic BAT dysfunction, in association with a low survival rate after TAC. Metabolomic analysis showed that reduced BAT thermogenesis was associated with elevation of plasma trimethylamine N-oxide (TMAO) levels. Administration of TMAO to mice led to significant reduction of phosphocreatine and ATP levels in cardiac tissue via suppression of mitochondrial complex IV activity. Genetic or pharmacological inhibition of flavin-containing monooxygenase reduced the plasma TMAO level in mice, and improved cardiac dysfunction in animals with left ventricular pressure overload. In patients with dilated cardiomyopathy, body temperature was low along with elevation of plasma choline and TMAO levels. These results suggest that maintenance of BAT homeostasis and reducing TMAO production could be potential next-generation therapies for heart failure.

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis.

SignificanceMetformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin's glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.

Diagnosis of early gastric cancer using narrow band imaging and acetic acid.

AIM: To determine whether the endoscopic findings of depressed-type early gastric cancers (EGCs) could precisely predict the histological type. METHODS: Ninety depressed-type EGCs in 72 patients were macroscopically and histologically identified. We evaluated the microvascular (MV) and mucosal surface (MS) patterns of depressed-type EGCs using magnifying endoscopy (ME) with narrow-band imaging (NBI) (NBI-ME) and ME enhanced by 1.5% acetic acid, respectively. First, depressed-type EGCs were classified according to MV pattern by NBI-ME. Subsequently, EGCs unclassified by MV pattern were classified according to MS pattern by enhanced ME (EME) images obtained from the same angle. RESULTS: We classified the depressed-type EGCs into the following 2 MV patterns using NBI-ME: a fine-network pattern that indicated differentiated adenocarcinoma (25/25, 100%) and a corkscrew pattern that likely indicated undifferentiated adenocarcinoma (18/23, 78.3%). However, 42 of the 90 (46.7%) lesions could not be classified into MV patterns by NBI-ME. These unclassified lesions were then evaluated for MS patterns using EME, which classified 33 (81.0%) lesions as MS patterns, diagnosed as differentiated adenocarcinoma. As a result, 76 of the 90 (84.4%) lesions were matched with histological diagnoses using a combination of NBI-ME and EME. CONCLUSION: A combination of NBI-ME and EME was useful in predicting the histological type of depressed-type EGC.

Usefulness of magnifying endoscopy with narrow-band imaging for diagnosis of depressed gastric lesions.

The usefulness of magnifying endoscopy with narrow-band imaging (ME-NBI) for the diagnosis of early gastric cancer is well known, however, there are no evaluation criteria. The aim of this study was to devise and evaluate a novel diagnostic algorithm for ME-NBI in depressed early gastric cancer. Between August, 2007 and May, 2011, 90 patients with a total of 110 depressed gastric lesions were enrolled in the study. A diagnostic algorithm was devised based on ME-NBI microvascular findings: microvascular irregularity and abnormal microvascular patterns (fine network, corkscrew and unclassified patterns). The diagnostic efficiency of the algorithm for gastric cancer and histological grade was assessed by measuring its mean sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy. Furthermore, inter- and intra-observer variation were measured. In the differential diagnosis of gastric cancer from non-cancerous lesions, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 86.7, 48.0, 94.4, 26.7, and 83.2%, respectively. Furthermore, in the differential diagnosis of undifferentiated adenocarcinoma from differentiated adenocarcinoma, the mean sensitivity, specificity, PPV, NPV, and accuracy of the diagnostic algorithm were 61.6, 86.3, 69.0, 84.8, and 79.1%, respectively. For the ME-NBI final diagnosis using this algorithm, the mean κ values for inter- and intra-observer agreement were 0.50 and 0.77, respectively. In conclusion, the diagnostic algorithm based on ME-NBI microvascular findings was convenient and had high diagnostic accuracy, reliability and reproducibility in the differential diagnosis of depressed gastric lesions.

18F-FDG uptake in primary gastric malignant lymphoma correlates with glucose transporter 1 expression and histologic malignant potential.

Positron emission tomography (PET) is used for staging and response evaluation in primary gastric lymphoma (PGL). However, the implications of [(18)F]-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in PGL at first diagnosis have not been reported. The relationship between (18)F-FDG uptake and the expression of facilitative glucose transporters (GLUTs), hexokinase II (HK II), and Ki67, as well as malignant potential in PGL, was assessed in this study. We analyzed 23 patients with PGL [nine with diffuse large B-cell lymphoma (DLBCL); seven with high-grade mucosa-associated lymphoid tissue (MALT) lymphoma; and seven with low-grade MALT lymphoma]. The expression levels of GLUT1, GLUT3, HK II, and Ki67 were evaluated according to the percentage of positive area determined by immunohistochemistry. Standardized uptake values correlated significantly with pathological malignant potentials (low-grade/high-grade MALT lymphoma and DLBCL: p = 0.001-0.002), Ki67 (p < 0.001), and GLUT1 expression (p = 0.02). We determined that (18)F-FDG uptake is related to GLUT1 expression and tumor histological grade as well as Ki67 in PGL.

Comparison between endoscopic macroscopic classification and F-18 FDG PET findings in gastric mucosa-associated lymphoid tissue lymphoma patients.

PURPOSE: The aim of this study was to compare endoscopic macroscopic classification with fluorine-18 fluorodeoxyglucose (F-18 FDG) uptake in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and to investigate the usefulness of F-18 FDG positron emission tomography (PET) for diagnosing gastric MALT lymphoma. MATERIALS AND METHODS: Sixteen patients with gastric MALT lymphoma who underwent F-18 FDG PET and gastrointestinal imaging modalities were included in this study. Sixteen healthy asymptomatic participants undergoing both F-18 FDG PET and endoscopy for cancer screening were in the control group. We investigated the difference of F-18 FDG uptake between the gastric MALT lymphoma and the control group and compared the uptake pattern in gastric MALT lymphoma with our macroscopic classification. RESULTS: The endoscopic findings of 16 gastric MALT lymphoma patients were classified macroscopically as chronic gastritis-like tumors (n = 6), depressed tumors (n = 5), and protruding tumors (n = 5). Abnormal gastric F-18 FDG uptake was observed in 63% of tumors in the gastric MALT lymphoma group and 50% of cases in the control group. The median maximum standardized uptake values for gastric MALT lymphoma patients and control group were 4.0 and 2.6, respectively, the difference of which was statistically significant (P = 0.003). F-18 FDG uptake results were positive for all protruding tumors but only 50% for chronic gastritis-like tumors and 40% for depressed-type tumors. CONCLUSIONS: F-18 FDG PET may be a useful method for evaluating protrusion-type gastric MALT lymphoma. When strong focal or diffuse F-18 FDG uptake is detected in the stomach, endoscopic biopsy should be performed, even if the endoscopic finding is chronic gastritis.

Extended indication criteria for endoscopic mucosal resection of early gastric cancer with special reference to lymph node metastasis--examination by multivariate analysis.

The purpose of this study was to clarify extended indication criteria of endoscopic mucosal resection (EMR) for early gastric cancer (EGC) by analyzing the independent risk factors involved in lymph node metastasis (LNM). Subjects were 422 patients who underwent gastrectomy with lymph node dissection for EGC at the Kurume University Hospital from 1994 to 2001. The EGCs were mucosal cancers (M) in 252 cases and submucosal cancers (SM) in 170 cases. Twelve clinico-pathological factors were assessed for their possible association with LNM. On univariate analysis, EGC with LNM showed the following characteristics: size; 3.1 cm or more, ulceration; present, heterogeneity; present, differentiation; poor, lymphatic vascular invasion; present, and invasion depth; SM2 (cancer penetration of submucosal layer, 0.5 mm or more from the muscularis mucosa). On multivariate analysis, the following four factors were identified as independent risk factors; invasion depth: Odds Ratio (OR) 10.9, lymphatic vascular invasion: OR 10.6, size: OR 3.2, and ulceration: OR 3.2. The incidence of LNM was 0% (0/141) (95% confidence interval, 0-2.6%) when these risk factors met the following four conditions: invasion depth; M or SM1 (cancer penetration of submucosal layer, less than 0.5 mm), lymphatic vascular invasion; absent, size; 3.0 cm or less, and ulceration; absent. It is concluded that EMR is a suitable radical treatment for EGC, and that the indication criteria for EMR can be extended depending on the results of the histological evaluation of the en bloc/total resected specimen concerning the above four factors for LNM.