記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background & Aims
In recent years, nonalcoholic steatohepatitis (NASH) has become a considerable healthcare burden worldwide. Pathogenesis of NASH is associated with type 2 diabetes mellitus (T2DM) and insulin resistance. However, a specific drug to treat NASH is lacking. We investigated the effect of the selective sodium glucose cotransporter 2 inhibitor (SGLT2I) ipragliflozin on NASH in mice.
Methods
We used the Amylin liver NASH model (AMLN), which is a diet-induced model of NASH that results in obesity and T2DM. AMLN mice were fed an AMLN diet for 20 weeks. SGLT2I mice were fed an AMLN diet for 12 weeks and an AMLN diet with 40 mg ipragliflozin/kg for 8 weeks. Results AMLN mice showed steatosis, inflammation, and fibrosis in the liver as well as obesity and insulin resistance, features that are recognized in human NASH. Ipragliflozin improved insulin resistance and liver injury. Ipragliflozin decreased serum levels of free fatty acids, hepatic lipid content, the number of apoptotic cells, and areas of fibrosis; it also increased lipid outflow from the liver.
Conclusions
Ipragliflozin improved the pathogenesis of NASH by reducing insulin resistance and lipotoxicity in NASH-model mice. Our results suggest that ipragliflozin has a therapeutic effect on NASH with T2DM.

DOI： 10.1371/journal.pone.0146337

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet.
Methods: eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed.
Results: Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet.
Conclusions: A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

DOI： 10.1186/s12876-015-0409-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background and AimMajor depressive disorder (MDD) is an important public health problem, and it is often comorbid with many chronic diseases. The purpose of this study was to identify the clinical features of non-alcoholic fatty liver disease (NAFLD) patients comorbid with MDD and to investigate the influence of MDD on the effect of treatment in patients with NAFLD.
MethodsA total of 258 patients with biopsy-proven NAFLD were included. MDD was diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. The patients were followed up for 48 weeks under standard care for NAFLD, which consisted mainly of lifestyle modification.
ResultsThere were 32 patients comorbid with MDD. They were characterized by more severe histological steatosis and higher NAFLD activity score, and also significantly higher levels of serum aminotransferase, -glutamyl transpeptidase and ferritin, than age-and-sex-matched NAFLD patients without MDD. Moreover, NAFLD patients with MDD showed poor response to the standard care for NAFLD, in body weight loss and in other parameters. Particularly, NAFLD patients with unstable MDD (not in full/partial remission) showed severe resistance to the treatment.
ConclusionThis is the first study to demonstrate the clinical features and response to therapy of NAFLD patients comorbid with MDD. The comorbid state of MDD was associated with more severe histological liver steatosis and worse treatment outcomes in patients with NAFLD. Further investigations are required to develop new lifestyle modification programs that enable NAFLD patients with MDD to achieve the treatment goal.

DOI： 10.1111/jgh.12897

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Although many of the factors and molecules closely associated with non-alcoholic steatohepatitis (NASH) have been reported, the role of inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) on the progression of NASH remains unclear. We therefore investigated the role of iNOS-derived NO in NASH pathogenesis with a long-term follow-up study using systemic iNOS-knockout mice under high-fat diet (HFD) conditions.
Methods: iNOS-knockout and wild-type mice were fed a basal or HFD for 10 or 48 weeks. Lipid accumulation, fibrosis, and inflammation were evaluated, and various factors and molecules closely associated with NASH were analyzed.
Results: Marked fibrosis and inflammation (indicators of NASH) were observed in the livers of iNOS-knockout mice compared to wild-type mice after 48 weeks of a HFD; however, lipid accumulation in iNOS-knockout mice livers was less than in the wild-type. Increased expressions of various cytokines that are transcriptionally controlled by NF-kB in iNOS-deficient mice livers were observed during HFD conditions.
Conclusions: iNOS-derived NO may play a protective role against the progression to NASH during an HFD by preventing fibrosis and inflammation, which are mediated by NF-kB activation in Kupffer cells. A lack of iNOS-derived NO accelerates progression to NASH without excessive lipid accumulation.

DOI： 10.1186/s12876-015-0269-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with increased risks of atherosclerotic diseases, including cardiovascular disease. However, the difference in risk between patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) has not yet been determined. Accumulating evidence has shown that high amounts of small dense low-density lipoprotein (sdLDL) are closely associated with atherosclerotic diseases. This study investigated differences in risk factors for atherosclerotic diseases, especially LDL-migration index (LDL-MI), an indicator of sdLDL, between patients with NAFL and NASH.
Methods: LDL-MI was analyzed in a primary cohort of 156 patients with NAFLD, including 53 with NAFL and 103 with NASH, and a validation cohort of 69 patients with NAFLD, including 25 with NAFL and 44 with NASH.
Results: In the primary cohort, NASH was associated with elevated LDL-MI (p=0.039). Multiple regression analysis showed that NASH and the non-use of lipid lowering medications were independently correlated with higher LDL-MI in all patients with NAFLD. Among patients not on lipid lowering medications, those with NASH had significantly higher LDL-MI than those with NAFL (p=0.001). These findings were confirmed in a validation cohort, in that LDL-MI was significantly higher in patients with NASH than with NAFL (p=0.043).
Conclusion:This study is the first to show that LDL-MI, an indicator of sdLDL, was higher in patients with NASH than with NAFL, suggesting that the risk of atherosclerotic diseases may be higher in NASH than NAFL. Patients with NASH should be followed closely, especially for the progression of liver pathology and atherosclerotic diseases.

DOI： 10.1371/journal.pone.0115403

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13c-acetic acid breath test. Methodology: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13(c) acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical com arison of the parameters tetween e two test conditions was formed. Results: No significant differences in the lated parameters, including T 1/2, T lag, GEC or beta and kappa, were observed between the two test conditions. Conclusions: The present study revealed that 0.1 mg mosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

DOI： 10.5754/hge13057

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13c-acetic acid breath test. Methodology: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13(c) acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical com arison of the parameters tetween e two test conditions was formed. Results: No significant differences in the lated parameters, including T 1/2, T lag, GEC or beta and kappa, were observed between the two test conditions. Conclusions: The present study revealed that 0.1 mg mosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

DOI： 10.5754/hge13057

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

Although therapeutic intervention for nonalcoholic steatohepatitis (NASH) at an early stage is important owing to the progressive nature of the disease, diagnosis using noninvasive methods remains difficult. We previously demonstrated NASH specific impairment of choline metabolism and the use of fasting plasma free choline (fCh) levels for NASH diagnosis. Here, we investigated the utility of an oral choline tolerance test (OCTT), based on disordered choline metabolism, as a novel noninvasive method for NASH diagnosis.
Sixty-five patients with biopsy proven nonalcoholic fatty liver disease (NAFLD) and 17 healthy controls were enrolled. Blood samples were obtained from all subjects five times during the OCTT (before and 1, 2, 3, and 4 h after oral loading with 260 mg choline).
Four-hour fCh levels after oral loading choline were markedly increased in NASH patients, compared with non-NASH subjects. For detecting NASH, compared with non-NASH subjects, the area under the curve for 4-h fCh levels was 0.829 on receiver operating characteristic (ROC) analysis. The cut-off level for NASH diagnosis was a parts per thousand yen0.16 mg/dL, and the sensitivity, specificity, positive predictive value, and negative predictive value were 80.1, 82.6, 78.4, and 84.4 %, respectively. Moreover, 4-h fCh levels were significantly associated with the disease activity based on NAFLD activity score in patients with NAFLD.
Four-hour fCh levels obtained by an OCTT reflect a NASH specific disorder of choline metabolism, suggesting that the OCTT is a novel and useful noninvasive method for diagnosing NASH at an early stage with sufficient accuracy for clinical practice.

DOI： 10.1007/s00535-013-0776-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AimRecently, several studies have shown the existence of associations between lipoprotein profiles and hepatitis C virus (HCV), although only a limited amount of information is available about the mechanisms underlying the changes in the lipoprotein profiles associated with HCV. In this study, we investigated the association between lipoprotein profile, classified according to the particle size, and lipoprotein metabolism.
MethodsWe used four kinds of cells for this experiment; full-length genome HCV RNA replicon cells (OR6), sub-genomic HCV RNA replicon cells (sO), and OR6c cells and sOc cells, which were the same cell lines treated with interferon-. The triglyceride (TG) levels in the lipoprotein subclasses of the culture medium were measured by high-performance liquid chromatography. The mRNA expression levels of several molecules associated with lipoprotein metabolism were measured in the OR6, OR6c, sO and sOc cells. To confirm some of the results obtained using the in vitro system, liver biopsy samples obtained from the patients were also examined.
ResultsThe content of TG in the large low-density lipoprotein (LDL) and medium LDL in the culture medium was increased only in the OR6 cells. The hepatic triglyceride lipase (HTGL) mRNA expression levels were lower in the OR6 cells than in the OR6c cells (P<0.01). Examination of the HTGL expression levels in the patients' livers revealed a decrease in HTGL expression in the chronic hepatitis C liver as compared with that in the chronic hepatitis B or non-alcoholic steatohepatitis liver (P<0.01).
ConclusionWe showed that HCV inhibits HTGL production in hepatocytes, inducing a change of the lipoprotein profile.

DOI： 10.1111/hepr.12072

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aims: The gastrointestinal motility effects of endogenous incretin hormones enhanced by dipeptidyl peptidase-IV (DPP-IV) inhibitors have not yet been sufficiently investigated. The aim of this study was to determine whether single pre-prandial sitagliptin, the DPP-IV inhibitor, administration might have an effect on the rate of liquid gastric emptying using the 13C-acetic acid breath test. Methods Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted for overnight and were randomly assigned to receive 50 mg sitagliptin 2 hours before ingestion of the liquid test meal (200 kcal per 200 mL, containing 100 mg 13C-acetate) or the test meal alone. Under both conditions, breath samples were collected for 150 minutes following the meal. Liquid gastric emptying was estimated by the values of the following parameters: the time required for 50% emptying of the labeled meal (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (Tlag), the gastric emptying coefficient and the regression-estimated constants (β and κ), calculated by using the 13CO2 breath excretion curve using the conventional formulae. The parameters between the 2 test conditions were compared statistically. Results No significant differences in the calculated parameters, including T1/2, Tlag, gastric emptying coefficient or ß and κ, were observed between the 2 test conditions. Conclusions The present study revealed that single-dose sitagliptin intake had no significant influence on the rate of liquid gastric emptying in asymptomatic volunteers. © 2013 The Korean Society of Neurogastroenterology and Motility.

DOI： 10.5056/jnm.2013.19.2.227

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AIMS: Liver inflammation is a risk factor for the progression of nonalcoholic fatty liver disease (NAFLD). However, the diagnosis of liver inflammation is very difficult and invasive liver biopsy is still the only method to reliably detect liver inflammation. We previously reported that overexpression of CD14 in Kupffer cells may trigger the progression to nonalcoholic steatohepatitis (NASH) via liver inflammation following hyper-reactivity to low-dose lipopolysaccharide. Therefore, the aim of this study was to investigate the relationship between soluble type of CD14 (sCD14) and histological features in patients with NAFLD. METHODS: Our cohort consisted of 113 patients with liver biopsy-confirmed NAFLD and 21 age-matched healthy controls. Serum sCD14 levels were measured by an enzyme-linked immunosorbent assay. RESULTS: Serum sCD14 levels were significantly associated with diagnosis of NASH and the area under the receiver operator characteristic curve (AUROC) to distinguish between not NASH and NASH was 0.802. Moreover, serum sCD14 levels were significantly associated with the disease activity based on NAFLD activity score and hepatic CD14 mRNA expression, which is correlated with membrane CD14 (mCD14) expression, in patients with NAFLD. In multiple regression analysis, the serum sCD14 levels were independently associated with liver inflammation. The AUROC to distinguish between mild and severe liver inflammation in patients with NAFLD was 0.752. CONCLUSIONS: We found that serum sCD14 levels increased significantly with increasing liver inflammation grade in patients with NAFLD, reflecting increased hepatic CD14 expression. Serum sCD14 is a promising tool to predict the worsening of liver inflammation, and may offer a potential biomarker for evaluation of therapeutic effects in NAFLD.

DOI： 10.1371/journal.pone.0065211

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: Choline is a dietary component that is crucial for normal cellular function. Choline is predominantly absorbed from the small intestine and completely metabolized in the liver. We recently demonstrated that free choline (fCh) levels in blood reflect the level of phosphatidylcholine synthesis in the liver and is correlated with the onset of non-alcoholic steatohepatitis (NASH). Our aim here was to validate the utility of this biomarker for NASH diagnosis. Methods: Our cohort consisted of 110 patients with biopsy proven non-alcoholic fatty liver disease (NAFLD) from four centers across Japan and 25 age-matched healthy controls. Plasma fCh levels were measured using high-performance liquid chromatography. Results: Patients with diagnosed or borderline NASH had significantly increased plasma fCh levels when compared with control subjects, or patients not diagnosed with NASH. Interestingly, an association between plasma fCh levels and expression of microsomal triglyceride transfer protein, which catalyzes the transfer of triglyceride, was reflected in the markedly negative correlation between these two variables in patients with NAFLD. Moreover, the grade of liver steatosis and fibrosis stage increased with increasing plasma fCh levels (P < 0.05). The area under the receiver-operating characteristic (ROC) curves for NASH, including borderline diagnosis, was 0.811. Additionally, the areas under the ROC for fibrosis stage were 0.816 for >stage 1, 0.805 for >stage 2, 0.809 for >stage 3 and 0.818 for >stage 4. Conclusion: Plasma fCh levels are closely related to the grade of liver steatosis and fibrosis, and predict NASH severity. Plasma fCh levels are therefore a potential diagnostic marker for early-stage NASH in clinical practice.

DOI： 10.1111/j.1872-034X.2012.00976.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：CELL PRESS  

Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.

DOI： 10.1016/j.cmet.2012.05.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

AIM: TO determine the effect of oral sumatriptan on gastric emptying using a continuous C-13 breath test (BreathID system).
METHODS: Ten healthy male volunteers participated in this randomized, 2-way crossover study. The subjects fasted overnight and were randomly assigned to receive a test meal (200 kcal/200 mL) 30 min after pre-medication with sumatriptan 50 mg (sumatriptan condition), or the test meal alone (control condition). Gastric emptying was monitored for 4 h after administration of the test meal by the C-13-acetic acid breath test performed continually using the BreathID system. Then, using Oridion Research Software (beta version), the time taken for emptying of 50% of the labeled meal (T-1/2) similar to the scintigraphy lag time for 10% emptying of the labeled meal (T-lag), the gastric emptying coefficient (GEC), and the regression-estimated constants (beta and kappa) were calculated. The statistical significance of any differences in the parameters were analyzed using Wilcoxon's signed-rank test.
RESULTS: In the sumatriptan condition, significant differences compared with the control condition were found in T-1/2 [median 131.84 min (range, 103.13-168.70) vs 120.27 min (89.61-138.25); P = 0.0016], T-lag [median 80.085 min (59.23-125.89) vs 61.11 min (39.86-87.05); P = 0.0125], and beta [median 2.3374 (1.6407-3.8209) vs 2.0847 (1.4755-2.9269); P = 0.0284]. There were no significant differences in the GEC or kappa between the 2 conditions.
CONCLUSION: This study showed that oral sumatriptan significantly delayed gastric emptying of a liquid meal. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i26.3415

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BAISHIDENG PUBL GRP CO LTD  

AIM: To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) resistant to transarterial chemoembolization (TACE).
METHODS: This study was conducted on 42 patients who received HAIC for advanced HCC between 2001 and 2010 at our hospital. 5-fluorouracil (5-FU) was administered continuously for 24 h from day 1 to day 5 every 2-4 wk via an injection reservoir. Intra-arterial cisplatin or subcutaneous interferon was administered in combination with the 5-FU. The patients enrolled in this retrospective study were divided into two groups according to whether or not they fulfilled the criteria for resistance to TACE proposed by the Japan Society of Hepatology in 2010 (written in Japanese); one group of patients who did not fulfill the criteria for TACE resistance (group A, n = 23), and another group who fulfilled the criteria for TACE resistance (group B, n = 19). We compared the outcomes in terms of the response and survival rates between the two groups.
RESULTS: Both the response rate and tumor suppression rate following HAIC were significantly superior in group A than in group B (response rate: 48% vs 16%, P = 0.028, tumor suppression rate: 87% vs 53%, P = 0.014). Furthermore, both the progression-free survival rate and survival time were significantly superior in group A than in group B (3-, 6-, 12-, and 24-mo = 83%, 70%, 29% and 20% vs 63%, 42%, 16% and 0%, respectively, P = 0.040, and 9.8 nno vs 6.2 mo, P = 0.040). A multivariate analysis (Cox proportional hazards regression model) showed that resistance to TACE was an independent predictor of poor survival (P = 0.007).
CONCLUSION: HAIC administrating 5-FU was not effective against advanced HCC resistant to TACE. Other tools for treatment, i.e., molecular-targeting agents may be considered for these cases. (C) 2012 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v18.i16.1933

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Before the introduction of capsule endoscopy and double-balloon endoscopy, there were no effective modalities for reliable evaluation of the small bowel. Recently, the SmartPill, a wireless pH/pressure recording capsule, has been utilized to measure:the whole gut transit time. However, there are few studies on the small bowel pH. The aim of this study was to investigate the relationship between small bowel disease and the small bowel pH, we designed a new modality, the "pH capsule", to non-invasively record sequential images and the pH. Methodology: Ten healthy male volunteers swallowed the "pH capsule" with 50mL of water. The "pH capsule" transmitted the acquired images and the pH to the recorder unit located outside the body for about ten hours while the subject was fasting. Results: All subjects completed this study. The intra-gastric pH was low and the pH in the whole small intestine was 7.61, 7.55: 7.2-8.1 (mean, median: range). The pH value increased from the duodenum to the terminal ileum (p<0.0001). Conclusions: We could non-invasively monitor sequential images and the pH of the small intestine with this new modality. The "pH capsule", is expected to become a valuable tool for clinical assessment of the small bowel.

DOI： 10.5754/hge11394

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD.
Methods: The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients. Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) x AST (IU/L)/(platelet count (10(9)/L) x root ALT (IU/L))
Results: Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only 6 of 308 patients with a FIB4 index below the proposed low cut-off point (< 1.45) were under-staged, giving a high negative predictive value of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (> 3.25) were over-staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies.
Conclusion: The FIB4 index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high negative predictive value for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point.

DOI： 10.1186/1471-230X-12-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ZHEJIANG UNIV  

Objective: The ideal medication for the treatment of acid-related diseases, e.g., peptic ulcers, stress-related gastric bleeding, functional dyspepsia, and gastroesophageal reflux disease, should have a rapid onset of action to promote hemostasis and relieve the symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of a proton pump inhibitor, omeprazole 20 mg, and an H-2-receptor antagonist, roxatidine 75 mg. Methods: Ten Helicobacterpylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 h after single oral administration of omeprazole 20 mg and roxatidine 75 mg. Each administration was separated by a 7-d washout period. Results: During the 6-h study period, the average pH after administration of roxatidine was higher than that after administration of omeprazole (median: 4.45 vs. 2.65; P=0.0367). Also during the 6-h study period, a longer duration of maintenance at pH above 2, 5, and 6 was observed after administration of roxatidine 75 mg than after administration of omeprazole 20 mg (median: 90.6% vs. 55.2%, P=0.0284; 43.7% vs. 10.6%, P=0.0125; 40.3% vs. 3.3%, P=0.0125; respectively). Conclusions: In Helicobacter pylori-negative healthy male subjects, oral administration of roxatidine 75 mg increased the intragastric pH more rapidly than that of omeprazole 20 mg.

DOI： 10.1631/jzus.B1100078

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2012/940384

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background and Aim: Diverticular hemorrhage is the common cause of lower gastrointestinal bleeding, and its incidence has been increasing in Japan. However, the exact cause of diverticular hemorrhage is not well understood. We investigated the risk factors for diverticular hemorrhage. Methods: We selected 103 patients with diverticular hemorrhage as cases and patients with colonic diverticulosis without a history of bleeding were selected as control subjects, exactly matched for age and gender. We collected the data from the medical records of each of the patients, such as those related to the comorbidities, medications and findings of colonoscopy, and conducted a matched case-control study to analyze the risk factors for diverticular hemorrhage. Results: Both groups were composed of 75 men and 28 women. The median age of the patients in both groups was 72.0 years (47.0-87.0). The body weight (p = 0.0065), body mass index (p = 0.006), prevalence of hypertension (p = 0.0242), prevalence of ischemic heart disease (p = 0.0015), and frequency of use of low-dose aspirin (p = 0.042) were significantly different between the two groups. The percentage of patients with bilateral diverticula, that is, diverticula on both the right and left hemicolon, was significantly higher in the diverticular hemorrhage group (p = 0.0011). Multiple regression analysis identified only the diverticular location as being significantly associated with the risk of diverticular hemorrhage (p = 0.0021). Conclusions: Only the diverticular location (bilateral) was found to be an independent risk factor for diverticular hemorrhage. Copyright (C) 2012 S. Karger AG, Basel

DOI： 10.1159/000336351

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KOREAN SOC NEUROGASTERONTEROL & MOTILITY  

Background/Aims
The administration of liquid nutrients to patients is often accompanied by complications such as gastroesophageal reflux. To prevent gastroesophageal reflux, high-viscosity liquid meals are used widely, however, it still remains controversial whether high-viscosity liquid meals have any effect on the rate of gastric emptying. The present study was conducted with the aim of determining whether high-viscosity liquid meals had any effect on the rate of gastric emptying and mosapride might accelerate the rate of gastric emptying of high-viscosity liquid meals.
Methods
Six healthy male volunteers underwent 3 tests at intervals of > 1 week. After fasting for > 8 hours, each subject received one of three test meals (liquid meal only, high-viscosity liquid meal [liquid meal plus pectin] only, or high-viscosity liquid meal 30 minutes after intake of mosapride). A C-13-acetic acid breath test was performed, which monitored the rate of gastric emptying for 4 hours. Using the Oridion Research Software (beta version), breath test parameters were calculated. The study parameters were examined for all the 3 test conditions and compared using the Freidman test.
Results
Gastric emptying was significantly delayed following intake of a high-viscosity liquid meal alone as compared with a liquid meal alone; however, intake of mosapride prior to a high-viscosity liquid meal was associated with a significantly accelerated rate of gastric emptying as compared with a high-viscosity liquid meal alone.
Conclusions
This study showed that high-viscosity liquid meals delayed gastric emptying: however, mosapride recovered the delayed rate of gastric emptying by high-viscosity liquid meals.

DOI： 10.5056/jnm.2011.17.4.395

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KOREAN SOC NEUROGASTERONTEROL & MOTILITY  

Background/Aims
The effects of Histamine-2 receptor antagonists and proton pump inhibitors on the gastrointestinal motility have not yet been sufficiently investigated. The aim of this study was to determine the effects of intravenous bolus administration of famotidine and omeprazole on the rate of gastric emptying using the continuous C-13 breath test (BreathID system, Exalenz Bioscience Ltd, Israel).
Methods
Twelve healthy male volunteers participated in this randomized, 3-way crossover study. After fasting overnight, the subjects were randomly assigned to receive 20 mg of famotidine, 20 mg of omeprazole or 20 mL of saline alone by intravenous bolus injection before a test meal (200 kcal per 200 mL, containing 100 mg of C-13-acetate). Gastric emptying was monitored for 4 hours after the ingestion of test meal by the C-13-acetic acid breath test performed using the BreathID system.
Results
No significant differences in the calculated parameters, namely, the T-1/2, T-lag, GEC, beta and kappa, were observed among the 3 test conditions.
Conclusions
The study revealed that intravenous administration of gastric acid suppressant drugs had no significant influence on the rate of gastric emptying in comparison with that of saline alone as a placebo. Our results indicating the absence of any effect of either famotidine or omeprazole on accelerating the rate of gastric emptying suggest that both medications can be administered safely to patients suffering from hemorrhagic peptic ulcers who need to be kept nil by mouth from the viewpoint of possible acceleration of gastrointestinal motility in the clinical setting.

DOI： 10.5056/jnm.2011.17.3.287

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Background Relapse and spontaneous remission (SR) are characteristic features of autoimmune pancreatitis (AIP).
Aim and methods We conducted a study to determine if the predictive factors might be potentially related to the relapse in 70 consecutive AIP patients. Regarding SR, we studied the data of patients without corticosteroid treatment (CST).
Results CST was administered to 60% (42/70) of the patients; however, relapse was noted in 45.2% (19/42) of these patients. In 95% (18/19) of the AIP patients developing relapse, the relapse occurred within 3 years. The relapse rate was 80% (12/15) in the AIP patients administered CST for less than 12 months and 25.9% (7/27) in those administered CST for over 12 months (p < 0.01). The results of univariate analysis revealed significant association of relapse with the presence of jaundice, IgG4 seropositivity, presence of diffuse pancreas swelling, duodenal papillitis (DP), history of initial CST, and history of supportive treatment (p < 0.05), whereas multivariate analysis revealed that IgG4 seropositivity (OR 10.506, p = 0.0422) and the presence of jaundice (OR 6.945, p = 0.0174) are significant independent factors predictive of relapse in AIP patients. SR was recognized in 65.0% (13/20) of AIP patients without CST. The results of univariate analysis revealed that SR was associated with IgG4 seropositivity (p < 0.05), and multivariate analysis identified IgG4 seropositivity (OR 0.032, p = 0.0092) as a significant independent factor predictive of SR in these cases.
Conclusion AIP patients with IgG4 seropositivity and jaundice are at a higher risk of relapse and they could therefore be candidates for over 3 years of maintenance CST. AIP patients with IgG4 seronegativity have a high likelihood of SR.

DOI： 10.1007/s00535-011-0393-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Expression of the forkhead/winged helix family of transcription factor P3+ regulatory T cells (FOXP3(+) Treg), a master gene of regulatory T cells (Treg) is observed in patients with autoimmune pancreatitis (AIP). We investigated the usefulness of detection of FOXP3(+) Treg in the main duodenal papilla for differential diagnosis between AIP and pancreatic cancer (Pca).
Firstly, we determined the cut-off value of FOXP3 expression in duodenal papilla taken from the patients with AIP (n = 22) and chronic pancreatitis (n = 21). Data from 32 patients with AIP and 30 patients with Pca who had undergone endoscopic biopsy were then studied. The numbers of FOXP3(+) Treg-positive lymphocytes and IgG4-positive plasma cells per high-power field (HPF) were counted in all the histopathological specimens.
The areas under the receiver-operating characteristic (AUROC) curves for FOXP3(+) and IgG4 expression were 0.934 and 0.953, respectively. Cut-off values calculated based on AUROC data were 14/HPF in FOXP3 and 10/HPF in IgG4. Seropositivity for IgG4 was observed in 22 out of the 31 patients with AIP (sensitivity 71.0%, specificity 84.6%, accuracy 75.0%). Significant infiltration of the major duodenal papilla by FOXP3(+) lymphocytes (a parts per thousand yen14/HPF) was recognized in 18 of the 32 patients with AIP (sensitivity 56.3%, specificity 100%, accuracy 77.4%). Significant infiltration of the major duodenal papilla by IgG4-positive plasma cells (a parts per thousand yen10/HPF) was recognized in 27 of the 32 patients with AIP (sensitivity 84.4%, specificity 80.0%, accuracy 82.3%).
Observation of FOXP3(+) cells in the main duodenal papilla may be useful in the differential diagnosis between AIP and Pca.

DOI： 10.1007/s00534-010-0359-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KOREAN SOC NEUROGASTERONTEROL & MOTILITY  

Background/Aims
There are few reports on the correlation between chewing gum and the gastrointestinal functions. But previous report showed use of chewing gum to be an effective method for controlling gastrointestinal symptoms. The aim of this study was to determine the correlation between chewing gum and gastric emptying using the continuous real time C-13 breath test (BreathID system).
Methods
Ten healthy male volunteers participated in this randomized, 2-way crossover study. The subjects fasted overnight and were randomly assigned to chewing gum (Xylish, 2-3/1 tablet) for an hour following intake of a test meal (200 kcal/200 mL) or intake of the test meal alone. Gastric emptying was monitored for 4 hours after administration of the test meal by the C-13-acetic acid breath test performed continually using the BreathID system.
Results
No significant differences in the calculated parameters, namely, T-1/2 (median, 111.82 vs 109.26 minutes; P = 0.575), T-lag (median, 53.28 vs 56.53 minutes; P = 0.333), gastric emptying coefficient (median, 3.58 vs 3.65; P = 0.285), regression-estimated constant beta (median, 1.85 vs 1.80; P = 0.575) and regression-estimated constant kappa (median, 0.61 vs 0.62; P = 0.959) were observed between the test meal alone group and the test meal and chewing gum group.
Conclusions
This study showed that chewing gum had no effect on the rate of gastric emptying. Therefore, since chewing gum did not enhance the speed of gastric emptying, it may ameliorate gastrointestinal symptoms through other mechanisms, such as saliva and autonomic nervous system.

DOI： 10.5056/jnm.2011.17.2.174

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記述言語：英語   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

The factors involved in the progression of non-alcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) are not fully understood and thus it is urgently needed to elucidate these factors. Steatosis is not causal in the development of NASH, but rather it sensitizes the liver to the damaging effects of second hits such that stressors innocuous to a healthy liver lead to the development of NASH in the steatotic liver. In the previous study, most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, very-low-density lipoprotein (VLDL) synthesis, especially hepatic microsomal triglyceride transfer protein (MTP) mRNA expression, was impaired in the NASH group. Moreover, NASH showed significantly higher incidence of minor alley appearance compared with NAFL, indicating the possibility of association between NASH pathogenesis and decreased congenital MTP activity. MTP is one of the enzymes that transfer triglycerides to nascent apolipoprotein B, producing VLDL and removing lipid from the hepatocyte. A growing body of literature suggests that the measurement of hepatic MTP expression may be helpful for diagnosis; and moreover, hepatic MTP activator may be a possible therapeutic agent for the treatment of NASH.

DOI： 10.1254/jphs.10R14FM

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: To determine the correlation between domperidone and gastric emptying using the continuous real time C-13 breath-test (BreathID system), a novel non-invasive technique for measuring gastric emptying.
Methodology: Six healthy male volunteers participated in this randomized, two-way crossover study. Subjects fasted overnight and were randomly assigned to receive a test meal (400kcal per 400mL) 30 minutes after intake of domperidone (10mg) with 50mL of water or intake of 50mL of water alone. Gastric emptying was monitored for 4h after administration of the test meal by C-13-acetic acid breath test continually performed using the BreathID system. The time taken for emptying of 50% of the labeled meals (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag), the gastric emptying coefficient (GEC), and the regression-estimated constants (6 and K) were calculated. Differences in the parameters measured at two time-points were analyzed using the Wilcoxon's signed-rank test.
Results: No significant differences in calculated parameters (T lag, T1/2, GEC, beta or kappa) were observed between the treated and non-treated groups.
Conclusions: This study showed that domperidone had no effect on gastric emptying. The drug ameliorates nausea and vomiting via its antagonic activity against dopamine receptor. Therefore, domperidone probably ameliorates nausea through other mechanisms.

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

DOI： 10.1007/s00535-010-0356-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD).
To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled.
In the estimation group, 98 (55%) patients had NASH. Serum ferritin [a parts per thousand yen200 ng/ml (female) or a parts per thousand yen300 ng/ml (male)], fasting insulin (a parts per thousand yen10 mu U/ml), and type IV collagen 7S (a parts per thousand yen5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin a parts per thousand yen200 ng/ml (female) or a parts per thousand yen300 ng/ml (male) = 1 point, fasting insulin a parts per thousand yen10 mu U/ml = 1 point, and type IV collagen 7S a parts per thousand yen5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis.
NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

DOI： 10.1007/s00535-010-0305-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Liver abscess is recognized as a life-threatening disease. However, even in recent years, approximately 50% of liver abscess cases are considered to be cryptogenic. Here, we report a case of liver abscess associated with periodontal bacterial infection by Fusobacterium necrophorum, which is commonly found in the oropharyngeal flora. A 36-year-old man presented with fever and contrast-enhanced abdominal computed tomography revealed multiple liver abscesses. F.necrophorum was isolated from oral smears, liver aspirates and blood samples. Liver abscesses caused by periodontal bacterial infection are rare, however, the incidence is expected to increase in the future, as periodontitis is extremely common and is on the rise as one of the most common chronic infections in the world. A systemic survey including periodontitis may be required for the exact diagnosis of the source of infection.

DOI： 10.1111/j.1872-034X.2010.00748.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: ideally, medications for the treatment of acid-related diseases should have a rapid onset of action to promote hemostasis and the resolution of symptoms. The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral administration of lafutidine alone or combined with peppermint oil.
Methodology: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after a single oral administration of lafutidine (10mg) or the administration of lafutidine (10mg) with peppermint oil (0.64mL). Each administration was separated by a 7-day washout period.
Results: No significant difference in the average pH was observed during the 4-hour period after the combined administration of lafutidine and peppermint oil and after the administration of lafutidine alone (median gastric pH: 5.09 versus 5.29; p=0.3122).
Conclusions: In H. pylori-negative healthy male subjects, an oral dose of lafutidine combined with peppermint oil did not increase the intragastric pH faster than lafutidine alone.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background and Aim:
Differentiation of sclerosing cholangitis-associated autoimmune pancreatitis (SC-AIP), primary sclerosing cholangitis (PSC) and cancer of the hilar part of the bile duct (CHB) has been challenging. The aim of the present study was to evaluate characteristic intraductal ultrasonography (IDUS) features that could be used to discriminate SC-AIP from PSC and CHB.
Methods:
Six patients with SC-AIP, 10 patients with PSC and 12 patients with CHB were identified. We reviewed the following bile duct features observed using IDUS to determine their usefulness for differentiating SC-AIP from PSC and CHB: presence of symmetrical wall thickness, wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar.
Results:
IDUS results (SC-AIP, PSC, CHB) were as follows: wall thickness (mm), 3.7 +/- 0.9, 2.6 +/- 0.9, 2.8 +/- 0.0.6; presence of symmetrical wall thickness, 100% (6/6), 20% (2/10), 8.3% (1/12); presence of homogeneous internal foci, 100% (6/6), 10% (1/10), 8.3% (1/12); and presence of lateral mucosal lesions continuous to the hilar, 83.3% (5/6), 40%(4/10), 25% (3/12). Symmetrical wall thickness of the bile duct, homogeneous internal foci and lateral mucosal lesions continuous to the hilar were detected significantly more often among the patients with SC-PSC than among the patients with PSC or CHB (P < 0.05).
Conclusions:
IDUS findings, such as symmetrical wall thickness, presence of homogeneous internal foci and presence of lateral mucosal lesions continuous to the hilar can facilitate the differential diagnosis of SC-AIP from PSC and CHB.

DOI： 10.1111/j.1443-1661.2010.01039.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Aim:
The major limitation of capsule endoscopy (CE) has been the lack of a standardized and validated severity scale for mucosal injury. The aim of the present study was to verify the usefulness of quantifying small bowel mucosal changes associated with giving low-dose aspirin (LDA) using a CE scoring index.
Methods:
The CE score for small bowel mucosal injury was investigated to evaluate the severity of mucosal injury. Healthy volunteers and patients suspected of having small bowel disease were recruited for this study. The short-term LDA group (V + S-LDA group) consisted of volunteers who took low-dose aspirin for 14 days; this group was then compared with healthy volunteers who did not receive LDA treatment (V-Control group). The long-term LDA group (L-LDA group) consisted of patients with at least a 3-month history of daily LDA use; this group was compared with non-users of LDA (P-Control group).
Results:
The CE score was significantly higher in the V + S-LDA group than in the V-Control group. In the V-Control group, almost all the subjects were categorized as exhibiting a 'normal' change. 'Mild' changes were observed significantly more frequently in the V + S-LDA group than in the V-Control group. The CE score was significantly higher in the L-LDA group than in the P-Control group. 'Mild' or 'moderate or severe' changes were observed significantly more frequently in the L-LDA group than in the P-Control group.
Conclusion:
The CE scoring system was useful for evaluating LDA-associated small bowel mucosal disease activity and for objectively scoring the small bowel inflammatory disease state.

DOI： 10.1111/j.1443-1661.2010.01044.x

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000308654

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000313695

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：International Scientific Literature Inc.  

Background: A visceral fat area of more than 100 cm2 as measured by computed tomography (CT) at the umbilical level has been included as a criterion for obesity in all the proposed criteria for metabolic syndrome. However, CT cannot be used frequently because of radiation exposure. We evaluated the usefulness of measurement of the serum levels of nitric oxide (NO), instead of CT and the waist circumference, as a marker of abdominal visceral fat accumulation. Material/Methods: The study was carried out in 80 subjects. The serum levels of NO metabolites (nitrate/nitrite) were measured using the Griess reagent. Results: Simple and multiple regression analysis revealed that the serum levels of NO metabolites showed the greatest degree of correlation with the visceral fat area (r=0.743, p&lt
0.0001), and corresponded to a visceral fat area of 100 cm2, as determined using the ROC curve, was 21.0 μmol/ml (sensitivity 88%, specificity 82%)
this method was more sensitive than the waist circumference for evaluation of the visceral fat accumulation. Conclusions: Measurement of the serum levels of NO metabolites may be a simple, safe, convenient and reliable method for the evaluation of visceral fat accumulation in clinical diagnostic screening. © Med Sci Monit.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study was to evaluate the correlation between gastrointestinal symptoms and diet therapy.
Methodology: The subjects comprised of 8 patients who attended the diabetes division at Fujisawa City Hospital between April and June 2007. The subjects were diagnosed as having diabetes mellitus based on the results of a blood analysis. The body weight of the subjects was measured, and the subjects were asked to score their gastrointestinal symptoms according to the Frequency Scale for the Symptoms of GERD (FSSG) before and after diet therapy for 9 to 14 days.
Results: Diet therapy for diabetic subjects was effective for weight reduction. The total FSSG score was decreased, and the reduction in dysmotility-like symptoms was greater than the reduction in acid-reflux-related symptoms.
Conclusions: Diet therapy for mild diabetic patients also improves gastrointestinal symptoms.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Percutaneous endoscopic gastrostomy is the standard method for enteral feeding in patients predicted to require long-term enteral nutrition because of dysphagia. A direct techinique with gastropexy is available, in which oropharyngeal passage of the internal bumper can be avoided. The aim of this study was to assess the early complications of percutaneous endoscopic gastrostomy performed using the new direct technique.
Methodology: Between August 2005 and July 2009, 231 patients underwent percutaneous endoscopic gastrostomy at our hospital. We analyzed the clinical characteristics of the patients related to the development of early complications such as bleeding or local infection. Early complications were defined as complications occurring within 7 days of the percutaneous endoscopic gastrostomy.
Results: The study population comprised 231 patients: 157 men and 74 women (median age, 73 years; range, 28-92 years). The percutaneous endoscopic gastrostomy was performed using the pull-through technique in 134 of these patients (58%), whereas the direct technique with gastropexy was employed in the remaining 97 patients (42%). In the multiple logistic regression analyses, only the use/non-use of the direct technique was identified as a variable significantly associated with the incidence of bleeding (odds ratio 5.236, 95% confidence interval 1.040 - 26.316; p=0.0447) and the incidence of local infection (odds ratio 0.283, 95% confidence interval 0.100 - 0.802; p=0.0175).
Conclusions: Use of the direct technique for performing percutaneous endoscopic gastrostomy was associated with the increased incidence of the early complication of bleeding, but the decreased incidence of local infection.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：RADIOLOGICAL SOC NORTH AMERICA  

Purpose: To investigate the clinical usefulness of ultrasonography-based acoustic radiation force impulse (ARFI) elastography (ie, ARFI sonoelastography) in patients with a diagnosis of nonalcoholic fatty liver disease (NAFLD) and compare ARFI sonoelastography results with transient sonoelastography and serum fibrosis marker test results.
Materials and Methods: Written informed consent was obtained from all subjects, and the local ethics committee approved the study. Fifty-four patients with a liver biopsy-confirmed diagnosis of NAFLD (mean age, 50.6 years +/- 13.7) were examined. All patients with NAFLD and healthy volunteers underwent ARFI sonoelastography, transient sonoelastography, and serum liver fibrosis marker testing (hyaluronic acids, type IV collagen 7 S domain). Ten healthy volunteers underwent ARFI sonoelastography. ARFI sonoelastography results were compared with liver biopsy findings, the reference standard. ARFI sonoelastography findings were compared with liver biopsy, transient sonoelastography, and serum fibrosis marker test results. Student t testing was used for univariate comparisons; Kruskal-Wallis testing, for assessments involving more than two independent groups; and areas under the receiver operating characteristic curve (A(z)), to assess the sensitivity and specificity of ARFI sonoelastography for detection of stage 3 and stage 4 fibrosis.
Results: Median velocities in the patients with NAFLD were 1.040 m/sec for those with stage 0 fibrosis, 1.120 m/sec for those with stage 1, 1.130 m/sec for those with stage 2, 1.780 m/sec for those with stage 3, and 2.180 m/sec for those with stage 4. The A(z) for the diagnosis of hepatic fibrosis stages 3 or higher was 0.973 (optimal cutoff value, 1.77 m/sec; sensitivity, 100%; specificity, 91%), while that for the diagnosis of stage 4 fibrosis was 0.976 (optimal cutoff value, 1.90 m/sec; sensitivity, 100%; specificity, 96%). Significant correlations between median velocity measured by using ARFI sonoelastography and the following parameters were observed: liver stiffness measured with transient sonoelastography (r = 0.75, P < .0001), serum level of hyaluronic acid (r = 0.459, P = .0009), and serum level of type IV collagen 7 S domain (r = 0.445, P = .0015).
Conclusion: There is a significant positive correlation between median velocity measured by using ARFI sonoelastography and severity of liver fibrosis in patients with NAFLD. The results of ARFI sonoelastography were similar to those of transient sonoelastography. (C) RSNA, 2010

DOI： 10.1148/radiol.10091662

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Hepatocellular carcinoma (HCC) is one of the most common neoplasms worldwide. Portal vein tumor thrombosis (PVTT) is a common complication of advanced HCC, and the prognosis of advanced HCC with PVTT is extremely poor. We report a case of HCC with PVTT evaluated by contrast-enhanced ultrasonography (CEUS) before and after hepatic arterial infusion chemotherapy (HAIC). A 59-year-old man with chronic hepatitis C was admitted to our hospital. CEUS clearly showed the thread and streaks sign in a solid lesion that occupied the right main branch of the portal vein. HAIC was performed, and CEUS after HAIC clearly showed disappearance of the thread and streaks sign. CEUS was very useful in diagnosing PVTT and in evaluating the effectiveness of HAIC in this case.

DOI： 10.1007/s10396-010-0259-6

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-LISS  

Metformin is widely used for the treatment of diabetes mellitus. Adenosine monophosphate-activated protein kinase (AMPK) is known to be activated by metformin and to inhibit the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the protein translational machinery and cell proliferation. We examined the effect of metformin on the suppression of colorectal carcinogenesis in chemical carcinogen-induced models. Seven-wk-old BALB/c mice were intraperitoneally (i.p.) injected with azoxymethane (AOM, 10 mg/kg) and then treated with or without metformin (250 mg/kg/d) for 6 wk (for the investigation of aberrant crypt foci [ACF] formation) or 32 wk (for polyp formation). We next investigated colonic epithelial proliferation using bromodeoxyuridine (BrdU) and the proliferating cell nuclear antigen (PCNA) labeling indices. Furthermore, to examine the indirect effect of metformin, the insulin resistance status and the serum lipid levels were assessed. Treatment with metformin significantly reduced ACF formation. The effect of metformin on colon polyp inhibition was relatively modest. No significant difference in body weight or glucose concentration was observed. The BrdU and PCNA indices decreased in mice treated with metformin. A Western blot analysis revealed that the phosphorylated mTOR, S6 kinase, and S6 protein levels in the colonic mucosa decreased significantly in mice treated with metformin. In conclusion, metformin suppresses colonic epithelial proliferation via the inhibition of the mTOR pathway through the activation of AMPK. As metformin is already used daily as an antidiabetic drug, it might be a safe and promising candidate for the chemoprevention of colorectal cancer. (c) 2010 Wiley-Liss, Inc.

DOI： 10.1002/mc.20637

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: Although non-alcoholic fatty liver disease (NAFLD) is now a common cause of chronic liver disease, discriminating between simple steatosis and non-alcoholic steatohepatitis (NASH), especially early-stage NASH, remains difficult. We investigated the clinical usefulness of measuring the spleen volume as a marker of early-stage NASH.
Methods: We evaluated computed tomography (CT) images obtained in 84 patients with histologically diagnosed NAFLD (22 with simple steatosis, 62 with NASH with mild fibrosis [stages 1-2]). We defined the data obtained by the following formula as a spleen-body index (SBI): SBI = maximal CT axial section area of the spleen (cm(2))/body surface area (BSA) (cm(2)) x 10(4). We compared the SBI between patients with simple steatosis and those with NASH with mild fibrosis.
Results: The mean SBI of the simple steatosis group was 15.8 +/- 3.9, while that of the NASH with mild fibrosis group was 18.7 +/- 5.7. This difference between the two groups was significant (P = 0.0314). A multiple logistic regression analysis showed that the SBI was significantly correlated with the discrimination of simple steatosis and NASH with mild fibrosis. The area under the receiver-operator curve was 0.661 for distinguishing between simple steatosis and NASH with mild fibrosis (P = 0.026, 95% confidence interval = 0.532-0.789).
Conclusion: Spleen enlargement may be a distinct feature of NASH, especially early-stage NASH. SBI might be a non-invasive and simple method of differentiating NASH and simple steatosis.

DOI： 10.1111/j.1872-034X.2010.00643.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim:
Congenital extrahepatic portosystemic shunt (CEPS) is a rare anomaly in which the enteric blood bypasses the liver and drains into the systemic veins through various venous shunts. Patients with CEPS often have liver tumors and complications such as cardiac or other anomalies, but portosystemic encephalopathy and gastrointestinal bleeding occur only occasionally. The clinical problems differ for each individual with CEPS, and establishing a prognosis can be very difficult.
Methods:
We reviewed the clinical features of 136 reported cases of CEPS and classified these cases according to their portosystemic shunts.
Results:
We classified portal blood flow directly into the inferior vena cava (IVC) as type A (88 cases), portal blood flow into the renal vein as type B (36 cases), and portal blood flow into the iliac vein via an inferior mesenteric vein as type C (12 cases). Type A patients were complicated with cardiac anomalies at a higher rate than other types. Type C patients had lower prevalences of cardiac anomalies and portosystemic encephalopathy than the other types, but the prevalence of gastrointestinal bleeding was significantly higher (P < 0.0001). The prognosis of CEPS has improved, and only six deaths have been previously reported, all of which occurred in type A patients.
Conclusions:
We reviewed the previously reported cases of CEPS. Classification according to the portosystemic shunt system might be useful for investigating the clinical features of CEPS.

DOI： 10.1111/j.1872-034X.2010.00667.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim:
Non-alcoholic steatohepatitis (NASH) is considered a hepatic manifestation of metabolic syndrome. However, effective drug therapy for NASH has not been established yet. In the present study, we evaluated the efficacy of 6 months of ezetimibe treatment for NASH patients with dyslipidemia for the comparison of improvement of the clinical parameters and histological alterations.
Methods:
We prospectively evaluated 10 consecutive NASH patients with dyslipidemia who agreed to participate in this study. The patients were given ezetimibe (10 mg/day) for 6 months, and clinical parameters and histological alterations were comparatively evaluated before and after treatment. All the patients were given standard calorie diet (30 kcal/kg per day, carbohydrate 50-60%, fat 20-30%, protein 15-20%) and exercise counseling from 3 months before the ezetimibe treatment.
Results:
The serum aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase, low-density lipoprotein cholesterol, high-sensitivity C-reactive protein and type IV collagen 7 s levels were significantly improved by the treatment with ezetimibe for 6 months. In histological observations, follow-up liver biopsies revealed that the NAS score and steatosis grade were also significantly improved. The fibrosis stage did not change significantly, but six of the 10 patients exhibited an improvement in their fibrosis stage.
Conclusion:
Major clinical parameters and histological observations were significantly improved by the treatment with ezetimibe. Our pilot study demonstrated the efficacy of ezetimibe for drug therapy of NASH and may lead to a large-scale clinical trial in the future.

DOI： 10.1111/j.1872-034X.2010.00644.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS AS  

Objective. The role of gastric acid reflux is difficult to separate from that of pancreatic-biliary reflux in the pathogenesis of erosive esophagitis (EE) and Barrett's esophagus (BE). Gastric surgery patients provide a good mode. for both significant pancreatic-biliary reflux and marked gastric acid inhibition. We assessed the risk of EE and BE after distal gastrectomy in a case-controlled study. Material and methods. One hundred and sixty patients (121 men, 39 women; median age 68 years; range 32-86 years) with distal gastrectomies (Billroth-I) and 160 sex- and age-matched controls with intact stomachs were enrolled. The presence of EE and BE were diagnosed based on the Los Angeles Classification and the Prague C & M Criteria, respectively. A conditional logistic regression model with adjustments for potential confounding factors was used to assess the associations. Results. According to the multivariate analyses, patients with distal gastrectomies tended to have inverse associations with the risks of EE and BE, and the inverse association with the risk of BE reached a significant level. Conclusions. Distal gastrectomy is not a risk factor for the development of BE and BE. This lack of a. positive association between distal gastrectomy and BE and BE may suggest that pancreatic-biliary reflux with a limited amount of acid is not sufficient to damage the esophageal mucosa.

DOI： 10.3109/00365520903536507

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Paraganglioma, a sporadically occurring rare tumor should be included in the differential diagnosis of retroperitoneal tumors, such as malignant lymphomas, gastrointestinal stromal tumors, sarcoma and carcinoma of unknown primary site. A 58-year-old Japanese woman presented with a large retroperitoneal tumor detected by ultrasonography (US). She had no medical history of hypertension. Computed tomography showed a mass, 7 cm in diameter, located between the pancreas and the inferior vena cava. It was unclear whether the mass originated from the duodenum or the mesentery. Endoscopic ultrasonography (EUS) demonstrated a large solid paraduodenal mass. Doppler US revealed sparse vascularity in the tumor. With the differential diagnosis of retroperitoneal tumor, we carried out EUS-FNA. At the time of the third needle puncture, transient severe hypertension was noted, with a blood pressure measurement of 269/130 mmHg. Data obtained from urine and blood examinations after EUS-fine-needle aspiration indicated a diagnosis of paraganglioma.

DOI： 10.1111/j.1443-1661.2010.00939.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Iron is regarded as a putative element that interacts with oxygen radicals, and high rates of hyperferritinemia and increased hepatic iron stores have been demonstrated in NASH. We investigated serum ferritin concentrations, HFE gene mutations, and insulin resistance in Japanese NASH patients and the diagnostic utility of serum ferritin concentrations as a means of distinguishing NASH. Serum ferritin concentrations were measured in 86 patients with histopathologically verified NAFLD (24 with steatosis and 62 with NASH) and 20 control subjects, they were tested for HFE gene mutations and their insulin resistance was measured. The serum ferritin concentration was significantly higher in the NASH patients than in the patients with simple steatosis (P = 0.006). There was no significant difference between the groups in HFE gene mutation (C282Y, H63D, and S65C), and the serum ferritin level was related with insulin resistance. The area under the ROC curve was 0.732 for distinguishing NASH from simple steatosis (P = 0.005; 95% CI, 0.596-0.856). In conclusion high serum ferritin concentrations are a distinguishing feature of Japanese NASH patients independent of HFE gene mutations.

DOI： 10.1007/s10620-009-0771-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Background. The pathogenesis of nonalcoholic steatohepatitis (NASH) is still unclear. Recently, the 2-hit hypothesis was proposed, in which nitric oxide production, representing oxidative stress, was proposed as a very important candidate for the second hit.
Methods. The total study period was 10 weeks. A total of 20 rats were randomly divided into 2 groups. Group 1 was administered the Choline-Deficient, l-Amino Acid-Defined diet to produce a NASH model, and Group 2 as control received the Choline-Sufficient, l-Amino Acid-defined diet. The blood and tissue concentrations of nitrate + nitrite were measured using the Griess reagent and the expression levels of inducible nitric oxide synthase (iNOS) proteins and mRNA was determined by Western blotting.
Results. In regard to nitric oxide (NO) and NO metabolites, there were significant differences in the blood (especially portal venous blood) as well as tissue (liver and visceral fat) concentrations between the 2 animal groups; the amounts of NO metabolites in the tissues were much higher in the NASH models. The level of nitrotyrosine was much markedly higher in the NASH models than in the controls. In regard to the tissue expression of iNOS a significant difference between the 2 groups was found in the visceral fat, especially in the mesenterium.
Conclusions. Based on these results, we hypothesize that the iNOS expression and NO levels in the visceral fat increase, with increased diffusion of NO and its metabolites into the liver, resulting in increased nitrotyrosine formation in the liver; this, in turn, induces inflammation, apoptosis, and fibrosis in the liver, which are one of the characteristic features of NASH.

DOI： 10.1111/j.1530-0277.2008.00756.x

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DOI： 10.1097/MPA.0b013e3181bc119d

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BAISHIDENG PUBLISHING GROUP INC  

AIM: To test the hypothesis that the shape and length of Barrett's epithelium are associated with prevalence of erosive esophagitis.
METHODS: A total study population comprised 869 patients who underwent endoscopy during a health checkup at our hospital. The presence and extent of Barrett's epithelium were diagnosed based on the Prague C & M Criteria. We originally classified cases of Barrett's epithelium into two types based on its shape, namely, flamelike and lotus-like Barrett's epithelium, and into two groups based on its length, its C extent < 2 cm, and >= 2 cm. Correlation of shape and length of Barrett's epithelium with erosive esophagitis was examined.
RESULTS: Barrett's epithelium was diagnosed in 374 cases (43%). Most of these were diagnosed as short-segment Barrett's epithelium. The prevalence of erosive esophagitis was significantly higher in subjects with flame-like than lotus-like Barrett's epithelium, and in those with a C extent of >= 2 cm than < 2 cm.
CONCLUSION: Flame-like rather than lotus-like Barrett's epithelium, and Barrett's epithelium with a longer segment were more strongly associated with erosive esophagitis. (C) 2010 Baishideng. All rights reserved.

DOI： 10.3748/wjg.v16.i4.484

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000297160

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000288508

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記述言語：英語   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.49.3233

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Aim:
Genetic factors as well as environmental factors play an important role in the development of non-alcoholic fatty liver disease (NAFLD). Recently, inducible nitric oxide synthase (iNOS) was significantly higher in the severest form of non-alcoholic steatohepatitis (NASH), and nitric oxide (NO) has been determined to play an important role in the process of fibrosis in NASH. In this study, we investigated iNOS gene polymorphisms for associations with NAFLD.
Methods:
A total of 115 NAFLD patients, consisting of 65 patients with NASH and 50 patients with simple steatosis, in whom a positive diagnosis had been made by liver biopsy, and 435 healthy control subjects, were recruited into this study.
Results:
We investigated 10 single nucleotide polymorphisms (SNP) of the iNOS gene, one of which, rs1060822, had the lowest P-value in the allele frequency model (P = 0.00078) with an odds ratio (95% confidence interval) of 0.49 (0.32-0.75). Four SNP, rs2297510, rs2297511, rs2797512 and rs1060822, were significantly associated with NAFLD, even when the most conservative Bonferroni's correction was applied. Linkage disequilibrium analysis revealed that SNP rs1060822 and three other SNP, rs2297510, rs2297511 and rs2797512, were in the same block. We also investigated associations between rs1060822 genotypes and the fibrosis index, and the results of the analysis revealed an additive increase in the fibrosis index and intrahepatic iNOS mRNA expression in the patients with the T allele of rs1060822.
Conclusion:
This is the first study to identify genetic variations in iNOS that may influence the risk of NAFLD and liver fibrosis in NAFLD.

DOI： 10.1111/j.1872-034X.2009.00539.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Hepatic mitochondrial beta-oxidation is considered to play a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH). The aim of this study was to determine whether there were differences between patients with NASH and healthy controls in a breath test with C-13-octanoate, a medium-chain fatty acid.
Methodology: The subjects were 8 patients (5 men, 3 women, median age 46.5 years) with histologically proven NASH and 6 healthy controls (5 men, 1 women, and median age 27.8 years). The C-13 breath test was performed for 4 hours using the BreathID system with a 100mL of water, containing 100mg C-13-octanoate.
Results: There were no significant differences between NASH patients and controls about all breath test; parameters.
Conclusions: NASH-mediated changes in breath test parameters after ingestion of C-13-octanoate were not observed in our study. The present study findings suggest the possible preservation of C-13-octanoate metabolism (mitochondrial beta-oxidation) in patients with NASH.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JOHN WILEY & SONS INC  

The specific mechanisms of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) pathogenesis remain unknown. In the present study we investigated the differences between NAFL and NASH in terms of liver lipid metabolites and serum lipoprotein. In all, 104 Japanese subjects (50 men and 54 postmenopausal women) with histologically verified NAFL disease (NAFLD) (51 with NAFL, 53 with NASH) were evaluated; all diagnoses were based on liver biopsy findings and the proposed diagnostic criteria. To investigate the differences between NAFL and NASH in humans, we carefully examined (1) lipid inflow in the liver, (2) lipid outflow from the liver, (3) very-low-density lipoprotein (VLDL) synthesis in the liver, (4) triglyceride (TG) metabolites in the liver, and (5) lipid changes and oxidative DNA damage. Most of the hepatic lipid metabolite profiles were similar in the NAFL and NASH groups. However, VLDL synthesis and lipid outflow from the liver were impaired, and surplus TGs might have been produced as a result of lipid oxidation and oxidative DNA damage in the NASH group. Conclusion: A growing body of literature suggests that a deterioration in fatty acid oxidation and VLDL secretion from the liver, caused by the impediment of VLDL synthesis, might induce serious lipid oxidation and DNA oxidative damage, impacting the degree of liver injury and thereby contributing to the progression of NASH. Therefore, dysfunctional VLDL synthesis and release may be a key factor in progression to NASH. (HEPATOLOGY 2009;50:772-780.)

DOI： 10.1002/hep.23094

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia, type 2 diabetes mellitus and hypertension, making it difficult to treat NAFLD effectively using any monotherapy available to date. In this study, we propose a novel combination therapy for NAFLD comprising ezetimibe (EZ), a cholesterol absorption inhibitor, and acarbose (AC), an alpha-glucosidase inhibitor.
Methods: C57BL/6J mice were divided into five treatment groups as follows: basal diet (1113), high-fat diet (HFD) only, HFD with EZ (5 mg/kg/day), HFD with AC (100 mg/kg/day), and HFD with both EZ and AC for 24 weeks.
Results: Long-term combination therapy with EZ and AC significantly reduced steatosis, inflammation and fibrosis in the liver, compared with long-term monotherapy with either drug, in an HFD-induced NAFLD mouse model; the combination therapy also significantly increased the expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferators-activated receptor-alpha 1 (PPAR-alpha 1) in the liver, compared with either monotherapy, which may have led to the improvement in lipid metabolic disorder seen in this model.
Conclusions: Combination therapy with EZ and AC for 24 weeks improved the histopathological findings in a mouse model of NAFLD. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jhep.2009.05.017

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Background
Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver.
Objective
In this study we investigated the association between angiotensin II type 1 receptor gene polymorphism (ATGR1) and NAFLD.
Methods
One hundred and sixty-seven NAFLD patients [106 with nonalcoholic steatohepatitis (NASH) and 61 with simple steatosis] with a positive diagnosis by liver biopsy and 435 healthy control subjects were recruited in this study.
Results:
We investigated 12 single nucleotide polymorphisms (SNPs) of the ATGR1 gene, among which rs3772622 showed the lowest P-value of allele frequency model (P=0.0000012) with an odds ratio (95% confidence interval) of 1.95 (1.49-2.55). Five SNPs (rs3772622, rs3772633, rs2276736, rs3772630 and rs3772627) were significantly associated with NAFLD, even when the most conservative Bonferroni's correction was applied. Linkage disequilibrium analysis revealed that SNP rs3772622 and another four SNPs (rs3772633, rs2276736, rs3772630 and rs3772627) were in the same block. We investigated the association between rs3772622 genotypes and the fibrosis index. The results of the analysis revealed an additive increase of the fibrosis index in the patients with the A allele of rs3772622.
Conclusions
This is the first report to demonstrate the genetic variations in ATGR1 that may influence the risk of NAFLD and liver fibrosis in NAFLD.

DOI： 10.1111/j.1478-3231.2009.01988.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: The association between obesity and the risk of Barrett's esophagus (BE) is unclear. Furthermore, the association between visceral obesity and the risk of BE is entirely unknown.
Methods: We conducted a retrospective study in 163 patients with non-alcoholic fatty liver disease (NAFLD) who underwent both endoscopy and abdominal CT at an interval of less than a year at our institution. BE was endoscopically diagnosed based on the Prague C & M Criteria. The surface areas of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were calculated from CT images at the level of the umbilicus. The correlations between the BMI, VAT, and SAT and the risk of BE were examined by univariate and multivariate analyses.
Results: Sixty-nine of the 163 study participants (42.3%) were diagnosed to have endoscopic BE, which was classified as short-segment BE (SSBE) in almost all of the cases. There were no significant differences in the age or gender distribution between the groups with and without BE. According to the results of the univariate analysis, VAT was significantly associated with the risk of BE; the BMI tended to be higher in the group with BE than in the group without BE, but this relation did not reach statistical significance. VAT was independently associated with the risk of BE even after adjustment for the BMI.
Conclusion: In Japanese patients with NAFLD, obesity tended to be associated with the risk of BE, and this risk appeared to be mediated for the most part by abdominal visceral adiposity.

DOI： 10.1186/1471-230X-9-56

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Aim:
We evaluated the characteristic endoscopic ultrasonography (EUS) findings of early autoimmune pancreatitis (AIP).
Methods:
Nineteen patients with AIP were identified from our database. We reviewed the following features of EUS as being potentially characteristic of early AIP: hyperechoic foci, hyperechoic strands, lobularity, hyperechoic pancreatic duct margins and reduced echogenicity. According to the Cambridge classification for chronic pancreatitis, we classified AIP into early AIP (Grades 0-2) and advanced AIP (Grades 3-5) and examined the histopathological findings in each stage of AIP.
Results:
There were nine cases of early AIP and 10 cases of advanced AIP. Five of the nine early cases of AIP showed spontaneous remission without corticosteroid therapy (P < 0.05). The EUS findings were as follows (early vs advanced): hyperechoic foci, 100% (9/9) vs 100% (10/10); hyperechoic strands, 66.7% (6/9) vs 70% (7/10); lobularity, 77.8% (7/9) vs 20% (2/10); hyperechoic pancreatic duct margin, 88.9% (8/9) vs 30% (3/10); reduced echogenicity, 88.9% (8/9) vs 90% (9/10). Lobularity and hyperechoic pancreatic duct margin were detected at a significantly higher frequency in early AIP than in the advanced AIP patients (P < 0.05). Regarding the histopathological findings, acinar cells were better preserved in the cases of early AIP, whereas acinar cells were reduced in number and replaced by massive fibrosis in the patients with advanced AIP.
Conclusions:
Lobularity and hyperechoic pancreatic duct margin are characteristic EUS features of early AIP, which has a more favorable prognosis, and shows a higher frequency of spontaneous remission and preservation of acinar cells, than advanced AIP.

DOI： 10.1111/j.1443-1661.2009.00879.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

The goal of this study was to investigate Cystatin SN, a cysteine protease inhibitor, as a novel tumor marker for colorectal cancer (CRC). Gene expression profiles of mRNA from normal tissues and cancer cell lines were performed. Twenty-eight monoclonal antibodies for Cystatin SN were generated and serum Cystatin SN was quantified using ELISA in sera from 159 patients with CRC and 40 healthy controls. Cystatin SN was highly expressed in colon cancer cells. Employing a receiver-operating characteristic curve, we obtained an area under the curve of 0.708 for Cystatin SN, 0.819 for carcinoembryonic antigen (CEA) and 0.703 for carbohydrate antigen 19-9 (CA19-9). The combination assay of Cystatin SN, CEA and CA19-9 showed 62.9% sensitivity and 90.0% specificity. Especially, the sensitivity of the combination assay in stages I and IT detection, in which stages curative operation would be possible, was improved over that of the assay testing only for CEA and CA 19-9 (from 37.5 to 42.5% in stage I, from 49.0 to 60.8% in stage II). Furthermore, Western blot analysis revealed that Cystatin SN was increased in the urine from patients with CRC. Our results suggest the possibility of utilizing this novel tumor marker that can be tested in urine samples. These observations suggest that Cystatin SN in combination with CEA and CA19-9 is a useful tumor marker for detecting early stage CRC and that it is a unique urinary excretory protein, suggesting that Cystatin SN might be a novel candidate for use in mass screening for CRC.

DOI： 10.3892/ijo_00000310

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

The antithrombotic effects of low-dose aspirin (LDA) are well established, and it is used for primary and secondary prevention of cardiovascular events. However, the small intestinal toxicity of LDA remains unclear. The aim of this study was to review the characteristics of small bowel injury in long-term LDA users with capsule endoscopy (CE).
We retrospectively reviewed all chronic LDA users (> 3 months) who underwent CE for suspected small bowel diseases from May 2004 to May 2008 at two medical centers.
At our institutions, a total of 22 patients (13 males and 9 females, mean age 66.3 years) taking LDA underwent a CE examination. The indications for CE were obscure gastrointestinal bleeding in 21 patients and 1 patient who had abdominal pain. Twenty-one patients (95.5%) had some small bowel mucosal injury. Small bowel erosions were identified in 14 patients (63.6%). This enteropathy was characterized by multiple petechiae, loss of villi, erosions, and ulcers with round, irregular, and punched-out shapes. Two patients had circumferential ulcers with stricture. In most patients, small bowel lesions were multifocal and were evenly distributed in the small bowel. No patients failed to pass the capsule.
This is the first CE report that has studied the characteristics of small bowel injury in chronic LDA users. CE is useful to diagnose small bowel enteropathy associated with LDA.

DOI： 10.1007/s00535-009-0040-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.

DOI： 10.1111/j.1872-034X.2009.00490.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

In human subjects, aberrant crypt foci (ACF) can be classified as dysplastic or non-dysplastic using magnifying colonoscopy. Dysplastic ACF are thought to be a biomarker for the risk of colorectal cancer (CRC). Hyperinsulinemia and insulin-like growth factor-1 (IGF-1) have also been reported to be associated with an increased risk of CRC. To clarify this association, we investigated the relationship between diabetes risk, IGF-1 and the number of dysplastic ACF. Assessment of the number of dysplastic ACF in the entire colorectum is technically difficult, and we imaged the lower rectum only. Blood collections were taken in the morning on the day of colonoscopy. A total of 512 ACF were counted in 84 male participants, and a correlation was demonstrated to exist between age, body mass index (BMI), fasting blood sugar (FBS), insulin, homeostasis model assessment-insulin resistance (HOMA-IR), plasma leptin levels, plasmal IGF-1 levels and the number of dysplastic ACF. A significant association between plasma IGF-1 levels and the number of dysplastic ACF was still demonstrable after adjustment for age, BMI, FBS, insulin, HOMA-IR and plasma leptin levels. Our findings suggest that increased plasma leptin and IGF-1 levels, hyperinsulinemia and insulin resistance may promote the growth of dysplastic ACF. The results of multiple regression analysis revealed that increased plasma IGF-1 levels are associated with the number of dysplastic ACF present, and may be an independent risk factor for CRC. In conclusion, elevated plasma IGF-1 may promote the growth of dysplastic ACF and play a key role in colon carcinogenesis in male individuals.

DOI： 10.3892/mmr_00000105

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The aim of the study was to evaluate bowel dysmotility in patients with a history of abdominal surgery by measuring both gastric transit time and small bowel transit time during capsule endoscopy and assessing the completeness of the examination. The study included 26 patients who had undergone abdominal surgery (postoperative group) and 52 patients who had not (control group). The capsule reached the cecum in 50.0% of the postoperative group and 80.8% of the control group (P = 0.005). While there was no significant difference in gastric transit time between the two groups (P = 0.882), small bowel transit time was significantly longer in the postoperative group (338.3 +/- A 119.2 min) than in the control group (266.4 +/- A 110.8 min, P = 0.010). This is the first study to report that the small bowel transit time during capsule endoscopy is prolonged in patients who had a history of abdominal surgery, resulting in a lower frequency of complete examination.

DOI： 10.1007/s10620-008-0467-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Coffee is one of the most popular beverages worldwide, however, few studies have examined the effects of coffee on the gastrointestinal system. The aim of this study was to determine whether there was a correlation between coffee intake and gastric emptying using a novel non-invasive technique for measuring gastric emptying with a continuous real time C-13 breath test (BreathID system: Oridion, Israel).
Methodology: Six healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to receive a test meal (200kcal per 200mL) plus postprandial 190mL black coffee or the test meal alone after fasting overnight. A C-13-acetic acid breath test was continuously performed using the BreathID system, which monitors gastric emptying, for 4 hours after the administration of the test meal. Using Oridion Research Software (13 version), the time for emptying of 50% of the labeled meals (T 1/2) and the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag) were calculated. The parameters between two occasions were compared using the Wilcoxon signed-rank test.
Results: After coffee intake the T 1/2 and T lag constant were significantly decreased.
Conclusions: The decrease in the T 1/2 and T lag suggests the acceleration of gastric emptying. This study showed that postprandial coffee intake enhances gastric emptying, suggesting the potential use of coffee in clinical settings for patients with functional gastrointestinal disorders.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: We aimed to estimate whether the macroscopic extent of gastric mucosal atrophy is associated with a risk for esophageal squamous cell carcinoma using a case-control study in Japanese subjects, a population known to have a high prevalence of CagA-positive H. pylori infection.
Methods: Two hundred and fifty-three patients who were diagnosed as having esophageal squamous cell carcinoma, and 253 sex-and age-matched controls were enrolled in the present study. The macroscopic extent of gastric mucosal atrophy was evaluated based on the Kimura and Takemoto Classification. A conditional logistic regression model with adjustment for potential confounding factors was used to assess the associations.
Results: Body gastritis, defined endoscopically, was independently associated with an increased risk for esophageal squamous cell carcinoma.
Conclusion: Our findings suggest that macroscopic body gastritis may be a risk factor for esophageal squamous cell carcinoma in Japan. Further studies are needed to confirm these findings.

DOI： 10.1186/1471-230X-9-34

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Spontaneous rupture is rare complication of hepatocellular carcinoma (HCC) with high mortality rate in cirrhotic cases. The aim of this study was to determine the factors influencing prognosis in cases of spontaneously ruptured HCC and to investigate the outcomes of the treatments employed, especially transcatheter arterial embolization (TAE).
Methods: A retrospective multicenter study was conducted in 48 cirrhotic patients with spontaneous rupture of HCC. Conservative treatment was employed in 32 patients (ConT group) and TAE was performed in 16 patients (TAE group).
Results: The median survival time (MST) in the ConT group was only 13.1 days and the survival rate was extremely poor: 59.4% at 7 days, 37.5% at 14 days, and 6.3% at 30 days. On the other hand, the MST in the TAE group was 244.8 days and the survival rate was 87.5% at 1 month, 56.3% at 3 months, 23.4% at 12 months, and 15.6% at 24 months. According to the results of univariate analyses, factors associated with poor hepatic function and poor suitability for TAE was important determinants of short-term death (less than 3 weeks) among the patients (p < 0.05). On the other hand, among the patients in whom initial TAE was successfully performed (n = 15), a multivariate analysis showed that a maximum tumor size not exceeding 7 cm was the only independent factor determining long-term survival (p = 0.0130).
Conclusion: Despite the inherent limitations of this retrospective study, TAE appears to be a useful treatment strategy for cirrhotic patients with spontaneous HCC rupture, as it yielded a longer survival period compared with conservative treatment in patients with ruptured HCC. Among the patients with ruptured HCC in whom initial TAE was successfully performed, the maximum tumor size was an important factor influencing survival.

DOI： 10.1186/1471-230X-9-29

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The ideal medication for treatment of acid related diseases should have a rapid onset of action to promote hemostasis. The aim of our study was to investigate the inhibitory effects on gastric acid secretion after single intravenous administrations of lansoprazole 30 mg and famotidine 20 mg.
Methodology: Twelve Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 4 hours after single intravenous administration of lansoprazole 30 mg or famotidine 20 mg.
Results: The average pH during the 4-hour period after administration of famotidine was higher than after lansoprazole (median: 5.15 versus 3.55, respectively; p = 0.0376). During the 4-hour study period, famotidine 20 mg provided a longer duration of pH > 3, 3.5, 4, 5, 6 and 7, compared to lansoprazole 30 mg (median: 73.6% versus 57.0%; p = 0.0414, 66.8% versus 47.8%; p = 0.0281, 60.8% versus 38.8%; p = 0.0150, 55.7% versus 29.7%; p = 0.0281, 45.0% versus 23.1%; p = 0.0414 and 23.9% versus 3.65%; p = 0.0076).
Conclusions: In Helicobacter pylori-negative healthy male subjects, an intravenous dose of famotidine 20 mg more rapidly increases intragastric pH than lansoprazole 30 mg.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

Adiponectin is a peptide hormone secreted by adipose tissue. It is a key hormone responsible for insulin sensitization, and its circulating level is inversely associated with abdominal obesity. Recent studies have shown that a reduced plasma adiponectin level is significantly correlated with the risk of various cancers. However, there are few studies regarding the association of adiponectin and colorectal cancer. To address this issue, we investigated the effect of adiponectin on colorectal cancer cells. Three colorectal cancer cell lines express both AdipoR1 and AdipoR2 receptors. MTT assay revealed that adiponectin inhibited human colorectal cancer cell growth. Furthermore, Western blot analysis revealed that adiponectin activated adenosine monophosphate-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR) pathways. Selective AMPK inhibitor compound C abrogated the inhibitory effect of adiponectin on cell growth. Our results clearly demonstrate the novel findings that adiponectin inhibits colorectal cancer cell growth via activation of AMPK, thereby down-regulating the mTOR pathway.

DOI： 10.3892/ijo_00000156

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL PUBLISHING, INC  

The association between obesity and the risk of colorectal cancer (CRC) cannot be easily evaluated because CRC itself is associated with a gradual loss of bodyweight. Aberrant crypt foci (ACF) can be classified as dysplastic ACF or non-dysplastic ACF by magnifying colonoscopy, and dysplastic ACF are thought to be a biomarker of CRC. Ninety-four participants who underwent colonoscopy at Yokohama City University Hospital, Japan, were enrolled in the current study. We detected 557 ACF, including 67 dysplastic ACF (12.0%). Univariate regression analysis was conducted to determine correlations between the number of dysplastic ACF and various potential risk factors, including patient age, waist circumference, body mass index, visceral fat area (VFA), and plasma adiponectin level. The results of multiple regression analysis revealed that the number of dysplastic ACF correlated with age (correlation coefficient r = 0.212, P = 0.0383) and plasma adiponectin level (r = -0.201, P = 0.0371), even after adjustments for sex, waist circumference, body mass index, and VFA. Our univariate correlation analysis data showed a significant correlation with the number of dysplastic ACF with VFA (r = 0.238, P = 0.0209), no correlation with subcutaneous fat area, and an inverse correlation with the plasma level of adiponectin (r = -0.258, P = 0.0118). Thus, our results suggest that aging and visceral fat accumulation could correlate moderately with colorectal carcinogenesis. The novelty of our study lies in the finding that visceral fat accumulation and a low plasma adiponectin level may promote colorectal carcinogenesis; therefore, these obesity-related parameters may serve as novel targets for CRC prevention. (Cancer Sci 2009; 100: 29-32).

DOI： 10.1111/j.1349-7006.2008.00994.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: In contrast to Western countries where erosive esophagitis (EE) is more prevalent in males, there is a high incidence of EE in elderly females in Japan. We aimed to examine the gender differences in the age-stratified prevalence of EE and Barrett's epithelium.
Methodology: The study population comprised 869 cases (463 men and 406 women) who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. EE was graded according to the Los Angeles Classification. Barrett's epithelium was diagnosed based on the Prague C & M Criteria.
Results: In contrast to the decrease of the proportion of EE with aging in males, that in females remained constant. The results suggest that the suppressive effect of the increased gastric mucosal atrophy associated with aging was wiped out by the age-related effect of the increased incidence of hiatal hernia. The proportions of Barrett's epithelium in both males and females increased with aging.
Conclusions: In Japan, the prevalence of elderly females complicated with hiatal hernia, which was partly due to osteoporosis and kyphosis, may affect the proportion of EE and probably Barrett's epithelium.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction. Penetration of the colon to the posterior uterine wall secondary to diverticulitis is unusual, with diagnostic methods not yet established. Non-invasive imaging, such as computed tomography and magnetic resonance imaging may help to establish a proper diagnosis, but confirmation may be reached only after surgical exploration. Case presentation. We report the case of a 78-year-old Japanese woman who presented with a low grade fever and mild diarrhea which occurred two or three times a week. Computed tomography and magnetic resonance imaging demonstrated a capsular lesion including an air structure with a diameter of 5 cm, between the posterior aspect of the uterine body and the sigmoid colon. A gastrograffin enema and colonoscopy demonstrated a giant diverticulum of the sigmoid colon with no evidence of malignancy. These data confirmed the diagnosis of diverticulitis complicated by a giant diverticulum. Because of a relapsing fever after therapy with antibiotics, the patient had en bloc surgical treatment of the uterus, fallopian tubes, ovaries and sigmoid colon, the organs involved in the diverticulitis, followed by an uneventful recovery. Conclusion. This is a rare case report of penetration of the sigmoid colon to the posterior uterine wall secondary to diverticulitis. © 2009 Akiyama et al.
licensee Cases Network Ltd.

DOI： 10.4076/1752-1947-3-8957

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000209218

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：KARGER  

Background and Aims: Small intestinal toxicity of low-dose aspirin remains unclear. The purpose of this capsule endoscopy study was to assess the incidence of small bowel injury in healthy volunteers treated with short-term low-dose aspirin. Methods: Healthy subjects were randomly assigned to receive low-dose aspirin for 14 days (Aspirin group) or no drugs for 14 days (Control group). The two treatment occasions were separated by a washout period of at least 4 weeks. All subjects underwent capsule endoscopy at the end of each treatment period. Results: After 2 weeks of treatment, the percentages of subjects with small bowel pathology were 80% in the Aspirin group compared with 20% in the Control group (p = 0.023). The incidence of small bowel mucosal breaks in the Aspirin group was higher than that in the Control group, although the difference was not significant (30 vs. 0%; p = 0.210). Conclusions: This is the first pilot study using capsule endoscopy to report on the relation between small bowel injury and low-dose aspirin. Among the healthy subjects, the short-term administration of low-dose aspirin was associated with a mild mucosal inflammation of the small bowel. Copyright (c) 2009 S. Karger AG, Basel

DOI： 10.1159/000204465

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記述言語：英語   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.48.2229

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記述言語：英語   出版者・発行元：JAPAN SOC INTERNAL MEDICINE  

DOI： 10.2169/internalmedicine.48.2823

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000227044

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0272-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MOSBY-ELSEVIER  

Background: Differentiating primary sclerosing cholangitis (PSC) and sclerosing cholangids caused by autoimmune pancreatitis (SC-AIP) is often challenging. Recently, endoscopic findings of the duodenal papilla in cases with AIP or PSC were reported by Unno and Parlak, although the endoscopic differentiation of these 2 conditions has not yet been fully clarified.
Objective: Our purpose was to clarify, the endoscopic findings of the duodenal papilla in patients with SC-AIP and those with PSC and to determine criteria for the differentiation of these conditions.
Design: Case series.
Setting: Restrospective.
Patients: Twenty-seven,en patients With SC-AIP and 12 patients with PSC who had undergone ERCP were identified from out database. We reviewed these records to determine whether the duodenal papillary findings (swollen papilla/normal papilla/small papilla) might be potentially useful for differentiating SC-AIP and PSC. Immunohistopathological findings for the duodenal papilla were also examined by using immunoglobulin G4 (IgG4) among the infiltrating plasma cells.
Interventions: ERCP, biopsy specimen taken from duodenal papilla.
Main Outcome Measurements: The presence of a swollen duodenal papilla with IgG4-positive plasma cells was useful for discriminating SC-AIP from with PSC.
Results: A swollen duodenal papilla was observed in 63% (17/27) of the patients with SC-AIP, whereas there was no swelling of the duodenal papilla of the patients with PSC. A small papilla was recognized in 50% (6/12) of the patients with PSC. IgG4-positive plasma cells in the duodenal papilla were significantly detected in the patients with SC-AIP but not in the patients with PSC.
Limitation: Single-center study.
Conclusions: Characteristic duodenal endoscopic papillary features in patients with SC-AIP, such as a swollen duodenal papilla and positive immunostaining for IgG4, might be helpful for discriminating this condition from PSC.

DOI： 10.1016/j.gie.2008.08.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: Non-alcoholic steatohepatitis (NASH) is a subset of non-alcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. In this study we analyzed the expression profile of genes and biological pathways involved in NASH in comparison with non-NASH by gene set enrichment analysis (GSEA) employing a DNA microarray technique.
Methods: mRNA from liver biopsy specimens was collected from a group of NASH patients and a group of non-NASH patients. We analyzed the relative abundance of mRNA using high-density oligonucleotide microarrays containing probes for 54 675 known genes, and investigated the pathogenetic mechanisms of NASH by means of a powerful technique for analyzing molecular profiling data, GSEA.
Results: The results showed that the level of expression of 27 gene sets was significantly higher and the level of expression of 25 gene sets was significantly lower in the NASH samples than in the non-NASH samples. Based on these results we created an online, publicly available, searchable database containing the data for the gene expression profiles of the NASH patients (http://www2.genome.rcast.u-tokyo.ac.jp/__/NASH/NASH_GSEA2/).
Conclusion: Our data revealed differences in expression of many gene sets that are involved in the pathogenesis of NASH.

DOI： 10.1111/j.1872-034X.2008.00399.x

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0273-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Evidence regarding the association between alcohol consumption and the gastro-esophageal reflux disease (GERD) spectrum has been conflicting. We examined the association between alcohol consumption and erosive esophagitis and Barrett's epithelium in Japanese men.
Methods: The study population comprised 463 men subjects who had undergone an upper endoscopy at the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The presence of erosive esophagitis and Barrett's epithelium was diagnosed based on the Los Angeles Classification and the Prague C and M Criteria, respectively. We divided the study population into four groups: never drinkers, light drinkers ( less than 25.0 g of ethanol per day), moderate drinkers ( 25.0 to 50.0 g of ethanol per day), and heavy drinkers ( more than 50.0 g of ethanol per day). A linear regression of the logistic regression analysis was used to analyze the dose-response trends.
Results: Compared with never drinkers, light drinkers ( less than 25.0 g ethanol per day), moderate drinkers ( 25.0 to 50.0 g per day), and heavy drinkers ( more than 50.0 g per day) had ORs for erosive esophagitis of 1.110 (95% CI: 0.553 - 2.228, p = 0.7688), 1.880 ( 95% CI: 1.015 - 3.484, p = 0.0445) and 1.988 ( 95% CI: 1.120 - 3.534, p = 0.0190), respectively. These groups had ORs for Barrett's epithelium of 1.278 ( 95% CI: 0.752 - 2.170, p = 0.3643), 1.458 ( 95% CI: 0.873 - 2.433, p = 0.1500), and 1.912 ( 95% CI: 1.185 - 3.086, p = 0.0079), respectively. The odds ratios/grams ( alcohol)/day of dose response trends for erosive esophagitis and Barrett's epithelium were 1.015 ( 95% CI: 1.004 - 1.026, p = 0.0066) and 1.012 ( 95% CI: 1.003 - 1.021, p = 0.0079), respectively.
Conclusion: These findings suggest that alcohol consumption in Japanese men tends to be associated with an increased risk of erosive esophagitis and Barrett's epithelium.

DOI： 10.1186/1471-230X-8-58

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記述言語：英語   出版者・発行元：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2008.04.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: The changes in the liver in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However it has remained difficult to differentiate between NASH and non-progressive NAFLD on the basis of the clinical findings alone.
Aims: In this study we investigated the clinical usefulness of plasma Pentraxin3 (PTX3) levels to predict NASH. Plasma PTX3 was measured in 70 patients with histologically verified NAFLD (28 with non-NASH and 42 with NASH) and 10 healthy control subjects.
Results: The plasma PTX3 level was significantly higher in the NASH cases than in the non-NASH cases (p = 0.0021) and control subjects (p = 0.045). And the plasma PTX3 level was significantly higher in the stages 3-4 NAFLD cases than in the stages 0-2 NAFLD cases (p<0.0001). The PTX3 values were closely correlated with the stages of liver fibrosis (p<0.0001, Kruskal-Wallis test). To detect NASH compared with non-NASH, the area under the curve for plasma PTX3 were 0.755, and to detect stages 3-4 NAFLD compared with stages 0-2 NAFLD, the area under the curve for plasma PTX3 were 0.850.
Conclusion: This is the first study to demonstrate consistent and profound elevation of plasma PTX3 levels in NASH in comparison with non-NASH. The results suggest that plasma PTX3 levels may not only be laboratory values that differentiate NASH from non-NASH, but marker of the severity of hepatic fibrosis in NASH.

DOI： 10.1186/1471-230X-8-53

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-activated transcription factor that has been implicated in the carcinogenesis and progression of various solid tumors, including pancreatic carcinomas. We aimed to clarify the role of this receptor in pancreatic cell motility in vitro and in metastasis in vivo. Cell motility was examined by assaying transwell migration and wound filling in Capan-1 and Panc-1 pancreatic cancer cells, with or without the PPAR gamma-specific inhibitor T0070907. A severe combined immunodeficiency xenograft metastasis model was used to examine the in vivo effect of PPAR gamma inhibition on pancreatic cancer metastasis. In both transwell-migration and wound-filling assays, inhibition of PPAR gamma activity suppressed pancreatic cell motility without affecting in vitro cell proliferation. Inhibition of PPAR gamma also suppressed liver metastasis in vivo in metastatic mice. In PPAR gamma-inhibited cells, p120 catenin accumulation was induced predominantly in cell membranes, and the Ras-homologous GTPases Rac1 and Cdc42 were inactive. Inhibition of PPAR gamma in pancreatic cancer cells decreased cell motility by altering p120ctn localization and by suppressing the activity of the Ras-homologous GTPases Rac1 and Cdc42. Based on these findings, PPAR gamma could function as a novel target for the therapeutic control of cancer cell invasion or metastasis. (Cancer Sci 2008; 99: 1892-1900)

DOI： 10.1111/j.1349-7006.2008.00904.x

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記述言語：英語   出版者・発行元：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2008.03.009

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記述言語：英語   出版者・発行元：SPRINGER  

DOI： 10.1007/s10620-008-0219-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

We report a rare case of adenosquamous carcinoma of the pancreas associated with humoral hypercalcemia of malignancy (HHM) in which parathyroid hormone-related protein (PTH-rP) was identified as the causative factor of hypercalcemia. A 72-year-old Japanese man was admitted to our institution complaining of fever and abdominal pain. Abdominal computed tomography demonstrated a large tumor in the body of the pancreas, with multiple liver metastases. Both serum calcium and PTH-rP levels were elevated. No accumulation was observed on bone scan with technetium-99. The patient died of pneumonia 3 months after admission. Autopsy demonstrated that the neoplasm in the pancreas showed an abrupt histological transition from adenocarcinoma to squamous cell carcinoma. PTH-rP was identified in the primary pancreatic tumor cells by immunohistochemical examination and a reverse-transcription polymerase chain reaction (RTPCR) method. We concluded that PTH-rP was the causative factor of the HHM, based on the laboratory data, immunohistochemical examination, and messenger RNA (mRNA) expression. This is a very rare report of adenosquamous cell carcinoma of the pancreas associated with HHM.

DOI： 10.1007/s00534-007-1258-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PROFESSOR D A SPANDIDOS  

Adiponectin is secreted by adipocytes and is a key hormone responsible for insulin sensitization. Recent studies have shown that plasma adiponectin is decreased in patients with breast, endometrial and gastric cancer. However, the effect of adiponectin on colorectal carcinogenesis is controversial. It is now well known that the adiponectin receptor exists in two isoforms, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). We examined the expression of the adiponectin receptors on normal colon mucosa and colon cancer tissues in a human study using real-time RT-PCR, Western blotting and immunohistochemical staining. Adiponectin receptors, AdipoR1/AdipoR2, were expressed in normal colon epithelial and colon cancer cells. Furthermore, laser microdissection was pet-formed to confirm our results. These results suggest that adiponectin may exert some effects on normal colon epithelium or colon cancer cells directly through adiponectin receptors. Further studies are required to elucidate the function of the AdipoRs activated by adiponectin and the downstream mechanisms of AdipoRs in colon cancer cells.

DOI： 10.3892/or_00000031

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Barrett's epithelium is currently believed to be related to acid gastroesophageal reflux. The aim was to determine the role of pancreatic-biliary reflux in the genesis of Barrett's epithelium.
Methodology: The study population comprised 1055 cases (606 men and 449 women; median age, 67years) who had undergone an upper endoscopy at 67 the Gastroenterology Division of Yokohama City University Hospital between August 2005 and July 2006. The study population was composed of 869 cases with intact stomachs and 186 cases with distal-gastrectomies. The presence and the progression of Barrett's epithelium were diagnosed based on the Prague C & M Criteria. The correlations of clinical factors, including distal-gastrectomy, with the presence and the progression of Barrett's epithelium were examined.
Results: The study demonstrated that 42.2% of the total population was diagnosed to have Barrett's epithelium and, in 12.6% of the cases with Barrett's epithelium, the progression of Barrett's epithelium was observed during the median 72 month follow-up. A distal gastrectomy was not significantly correlated with either the incidence or progression of Barrett's epithelium.
Conclusions: This lack of association between gastric surgery and Barrett's epithelium suggests that pancreatic-biliary reflux with limited acid is not sufficient for the genesis of Barrett's epithelium.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Hepatocellular carcinoma with portal venous invasion has a poor prognosis. We report a case treated successfully by intra-arterial 5-fluorouracil with systemic peglated-interferon-alpha-2b instead of conventional interferon-alpha.
A 66-year-old mail was admitted to our hospital, and diagnosed with hepatocellular carcinoma with portal venous invasion. Following informed consent,, he was treated with eight week cycles of combination chemotherapy using intra-arterial 5-fluorouracil (500mg/body/day i.a., days 1-5, 8-12 continuously) and pepylated-interferon-alpha-2b (100 mu g body s.c., days 1, 8). No significant side effects were observed during his therapy. After 4 cycles, computed tomography scan revealed a partial response of tumor reduction. This is the first report of advanced hepatocellular carcinoma effectively treated using subcutaneous pegylated-interferon-alpha-2b with intra-arterial 5-fluorouracil. While the conventional therapy of interferon-alpha with 5-fluorouracil has significant side effects, no significant side effects were observed in Our case. The use of subcutaneous pegylated-interferon-alpha-2b combined with intra-arterial 5-fluorouracil, may improve patients quality of life.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The aim of this study was to determine whether there was a correlation between body positions and gastric emptying, using a novel non-invasive technique for measuring gastric emptying with a continuous real time (13)C breath test (BreathID system).
Methodology: Ten healthy male volunteers participated in this randomized, two-way crossover study. On both occasions. the (13)C breath test was performed for 4 hours using the BreathID system with a liquid meal (200kcal per 200mL) containing 100mg (13)C-acetic acid. Subjects were randomly assigned to sit comfortable (the sitting position) or to lie supine (the lying position).
Results: In the lying position, T 1/2 and T lag were significantly delayed. The gastric emptying coefficient was also decreased in lying position.
Conclusions: This study showed that gastric emptying following a liquid meal was significantly delayed in the lying position compared to the sitting position, suggesting the potential use of these findings in the clinical setting for patients receiving enteral nutrition via the stomach.

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: Genetic factors as well as environmental factors are important in the development of NAFLD and in this study we investigated associations between polymorphisms of peroxisome proliferators-activated receptor gamma coactivator 1 alpha polymorphism (PPARGC1A) and NAFLD.
Aims: We recruited 115 patients with biopsy-proven NAFLD, 65 with NASH and 50 with simple steatosis, and 441 healthy control subjects and investigated 15 SNPs of PPARGC1A.
Results: SNP rs2290602 had the lowest p value in the dominant mode (p = 0.00095), and the odds ratio for NAFLD (95% CI) was 2.73 (1.48-5.06). rs2290602 was significantly associated with NAFLD even when the most conservative Bonferroni's correction was applied (p = 0.0143). The frequency of the T allele of rs2290602 was significantly higher in the NASH patients than in the control subjects (p = 0.00093, allele frequency mode), and its frequency in the NASH patients tended to be higher than in the simple steatosis patients (p = 0.09). The results of the real-time RT-PCR study showed that intrahepatic mRNA expression of PPARGC1A was lower in the TT group than in the GG or GT group at SNP rs2290602 (p = 0.0454).
Conclusion: This is the first study to demonstrate a significant association between genetic variations in PPARGC1A and NAFLD. This finding suggested that PPARGC1A polymorphism and lower expression of PPARGC1A mRNA in the liver are an important genetic contribution to etiology of NAFLD.

DOI： 10.1186/1471-230X-8-27

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

Background: The precise role of capsule endoscopy in the diagnostic algorithm of obscure gastrointestinal bleeding has yet to be determined. Despite the higher diagnostic yield of capsule endoscopy, the actual impact on clinical outcome remains poorly defined. The aim of this study was to evaluate the follow-up results of patients with obscure gastrointestinal bleeding to determine which management strategies after capsule endoscopy reduced rebleeding.
Methods: All patients in whom the cause of obscure gastrointestinal bleeding was investigated between May 2004 and March 2007 were studied retrospectively. We evaluated the clinical outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy using the rebleeding rate as the primary outcome.
Results: Seventy-seven patients with obscure gastrointestinal bleeding underwent capsule endoscopy. Capsule endoscopy identified clinically significant findings that were thought to be the sources of obscure gastrointestinal bleeding in 58.4% of the patients. The overall rebleeding rate was 36.4%. The rebleeding rate was significantly higher among patients with insignificant findings than among those with significant findings (p = 0.036). Among the patients in whom capsule endoscopy produced significant findings, the rebleeding rate of the patients who underwent therapeutic interventions was significantly lower than that in those who did not undergo intervention (9.5% vs 40.0%, p = 0.046).
Conclusion: Follow-up and further aggressive interventions are necessary for patients with obscure gastrointestinal bleeding and significant capsule endoscopy findings to reduce the chance of rebleeding.

DOI： 10.1186/1471-230X-8-12

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Background/Purpose. Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas have a favorable prognosis. However, invasive ductal carcinomas of the pancreas show a rapid progression. The aim of this study was to investigate gene mutations in pure pancreatic juice from IPMN patients and to define these genetic mutations in relation to the histopathological and clinical features of IPMNs.
Methods. Twenty-two patients with IPMN, 21 patients with ductal carcinoma, and 20 patients with normal pancreas or chronic pancreatitis were recruited for this study. We measured the main pancreatic duct's largest diameter and the maximum size of a dilated branch was assessed by ultrasonography or endoscopic ultrasonography. Pure pancreatic juice was collected and was investigated for K-ras, p16, and p53 mutations.
Results. Mutant K-ras gene was detected in 13 of the 22 patients (59.1%) with IPMNs. Different kinds of mutations were detected in the same patient in 4 cases. In the 13 patients with mutant K-ras gene, the diameter of the most dilated part of the main pancreatic duct was 2-8 mm ( average, 4.5 mm) and in 7 patients with wild-type K-ras gene, the diameter was 2 5 mm ( average, 2.7 mm). There was a significant difference in the diameter of the main pancreatic duct between patients with and without the mutant K-ras gene ( P = 0.0323).
Conclusions. The incidence of K-ras mutation may be associated with the hypersecretion of mucin.

DOI： 10.1007/s00534-007-1223-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

The aim of this study was to evaluate the relationship between the diagnosis of metabolic syndrome (MetS) or its components and the prevalence of microvascular and macrovascular complications in 130 Japanese type 2 diabetic patients. Out of the 130 patients, 58.5% satisfied the criteria of the MetS as defined by the IDF guideline. The results of logistic regression analysis with adjustment for three variables (age, gender and duration of diabetes) revealed that the presence of MetS as defined by the IDF guideline was not independently related to the presence of proliferative retinopathy, proteinuria, neuropathy, or macrovascular disease in the diabetic patients. The waist circumference per se was not associated with diabetic neuropathy, retinopathy, nephropathy, or macrovascular diseases. These results suggest that neither the presence of MetS, as defined by the IDF guideline, nor the waist circumference was associated with the presence of either microvascular or macrovascular complications in Japanese type 2 diabetic patients. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2007.10.035

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：W J G PRESS  

The differential diagnosis between intracystic hemorrhage and cystadenocarcinoma of the liver is often difficult even with the use of various imaging modalities. A 73-year-old woman was admitted to our hospital with the complaint of right upper quadrant pain. Ultrasonography (US) demonstrated a heterogeneous echogenic cyst measuring 11 cm x 8 cm in size in S2 of the liver, indicated intracystic hemorrhage of simple liver cyst or cystadenocarcinoma, but the differential diagnosis was considerably difficult. Levovist (Schering, Berlin, Germany) US revealed no enhancement of the intracystic structures, suggesting a clot in the case of intracystic hemorrhage. An operation was performed and the resected lesion showed a solitary benign liver cyst, measuring 5.5 cm x 4.7 cm x 8.5 cm containing a large blood clot. The patient had an uneventful recovery after the surgery. Levovist US may play an important role in discrimination between intracystic hemorrhage of simple hepatic cysts and cystadenocarcinoma of the liver. (C) 2008 WJG. All rights reserved.

DOI： 10.3748/wjg.14.805

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記述言語：英語  

We investigated the association between the serum level of gamma-glutamyltransferase (GGT) and parameters of adiposity and lipid profile, including the serum triglyceride (TG), HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels in Japanese patients with type 2 diabetes mellitus and non-diabetic subjects. A total of 257 Japanese subjects (169 patients with type 2 diabetes and 88 non-diabetic subjects) were enrolled in the study. To assess the hepatic fat content, the ratio of the CT attenuation value of the liver to that of the spleen (L/S ratio) was calculated. Serum GGT was significantly correlated with the waist circumference, BMI, visceral fat area (VFA), L/S ratio and TG, but not with the subcutaneous fat area (SFA). The serum GGT was still correlated with the VFA and TG, but not with the SFA, after adjustment for the four variables of age, gender, serum HbA1c and the L/S ratio. Our finding that the serum GGT is specifically associated with the VFA, but not with the SFA, suggests that the serum GGT may be useful as a convenient indicator of VFA in the clinical treatment of obesity. © 2007 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.diabres.2007.06.014

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000127417

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000140976

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000140975

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記述言語：英語  

DOI： 10.1159/000151298

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

The term nonalcoholic steatohepatitis (NASH) has recently been proposed to identify a fatty liver disease accompanied by diffuse fatty infiltration and inflammation. However, no drug therapy has been established for NASH as yet. In the present study, we demonstrate the effect of the angiotensin II type 1 receptor antagonist telmisartan on the development of NASH in a rat model. Telmisartan, but not the angiotensin receptor antagonist valsartan, markedly attenuated hepatic steatosis, inflammation, and fibrosis in these rats. The quantitative parameters of steatosis, inflammation, and fibrosis were also ameliorated by treatment with telmisartan. Compared with telmisartan, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone attenuated hepatic steatosis and fibrosis of the liver to a similar degree. However, telmisartan, but not pioglitazone, dramatically decreased both subcutaneous and visceral fat. In conclusion, these results indicated that telmisartan should be the drug of first choice for the treatment of patients with NASH.

DOI： 10.1007/s10620-007-9741-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER ASSOC CANCER RESEARCH  

Purpose: The risk of colorectal cancer is increased inpatients with inflammatory bowel diseases, especially those with ulcerative colitis (UC). Although 5-aminosalicylic acid (5-ASA) is widely used in the treatment of UC to suppress the colitic inflammation, no studies have. been conducted to examine the chemopreventive effect of 5-ASA, given in the remission phase of colitis, against colitis- associated cancer using animal models. We therefore investigated the possible inhibition by peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligands and 5-ASA of colitis-associated colon carcinogenesis in a mouse model.
Experimental Design: A dextran sodium sulfate/azoxymethane-induced mouse colon cancer model was used, and the chemopreventive effects of 5-ASA and PPAR-gamma ligands, given in the remission phase of colitis, against colitis-related colon carcinogenesis, were evaluated.
Results: The number of neoplasms in the mice treated with 5-ASA was significantly lower than that in the control mice. In addition, the size of the neoplasms in treated mice was also significantly smaller than that in the control mice. In contrast, no significant suppression in the number or size of the tumors was observed in the mice treated with PPAR gamma ligands. The proliferating cell nuclear antigen - labeling index in the tumor cells of the 5-ASA-treated mice was significantly smaller than that in the control, indicating that 5-ASA reduced tumor cell proliferation.
Conclusion: Our results revealed that 5-ASA given in the remission phase of colitis significantly suppressed the development of colitis-associated cancer in a mouse model, which indicates the clinical importance of adopting chemopreventive strategies even in UC patients in remission.

DOI： 10.1158/1078-0432.CCR-07-1208

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

Nonalcoholic steatohepatitis (NASH) is a subset of nonalcoholic fatty liver disease (NAFLD) and sometimes progresses to cirrhosis and liver failure. We analyzed the expression profiles of approximately 50,000 genes and biological pathways in NASH patients in comparison with simple steatosis patients by using the analytical technique of GSEA (Gene Set Enrichment Analysis) by DNA microarrays. Although expressions of various genes were altered, GSEA showed clearly lower expression of nuclear receptors, including the peroxisome proliferator-activated receptor gamma (PPAR gamma) pathway. In a preliminary study we therefore investigated the therapeutic effect of low-dose pioglitazone (15 mg/day per body for 24 weeks), a synthetic ligand for PPAR gamma, in 12 NASH patients. A decrease in aminotransferase (ALT) values to within the normal range was observed in 7 (58.3%) of the patients, and because the dose of pioglitazone was lower than that ordinarily used, no side effects, such as fatigue, lower extremity edema, or weight gain, were observed. In conclusion, the results confirmed involvement of the PPAR gamma pathway in NASH and the therapeutic utility of a PPAR gamma ligand.

DOI： 10.1254/jphs.FM0070063

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記述言語：英語   出版者・発行元：B M J PUBLISHING GROUP  

DOI： 10.1136/gut.2007.126417

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Background. The changes in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However, it has remained difficult to differentiate between NASH and nonprogressive NAFLD by clinical examination. We investigated the interrelationships between serum high-sensitivity C-reactive protein (hs-CRP) and the pathogenesis and progression of NASH. Methods. Hs-CRP was measured in 100 patients with histologically verified NAFLD (29 with steatosis and 71 with NASH), and a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to measure the intrahepatic mRNA expressions of CRP and interleukin (IL)-6. Results. The results of a multiple regression analysis revealed that in comparison with cases of steatosis, hs-CRP was significantly elevated (P = 0.0048) in cases of NASH. Furthermore, among patients with NASH, hs-CRP was significantly elevated in those with advanced fibrosis compared with that in those with mild fibrosis (P = 0.0384), even after adjustment for age, sex, presence of diabetes, body mass index, visceral fat area, subcutaneous fat area, homeostasis model assessment for insulin resistance, high-density lipoprotein cholesterol, triglyceride, and low-density lipoprotein cholesterol. The results of the RT-PCR analysis showed that intrahepatic mRNA expression of CRP, but not IL-6, was increased in patients with NASH compared with those with steatosis (P = 0.0228). Conclusions. This is the first report to demonstrate consistent and profound elevation of hs-CRP in cases of NASH compared with in cases of simple nonprogressive steatosis. Our results suggest that hs-CRP may be a clinical feature that not only distinguishes NASH from simple nonprogressive steatosis but also indicates the severity of hepatic fibrosis in cases of NASH.

DOI： 10.1007/s00535-007-2060-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Background. The aim of this study was to determine whether there was a correlation between peppermint oil and gastric emptying by using a novel noninvasive technique for measuring gastric emptying with a continuous real-time C-13 breath test (BreathID system, Oridion, Israel). Methods. Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to receive a test meal (200 kcal per 200 ml) containing 0.64 ml of peppermint oil or the test meal alone, after fasting overnight. A C-13-acetic acid breath test was continuously performed with the BreathID system, which monitors gastric emptying, for 4 h after the administration of the test meal. Using Oridion Research Software (beta version), the time for emptying of 50% of the labeled meals (T 1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (T lag), the gastric emptying coefficient (GEC), and the regression-estimated constants (beta and kappa) were calculated. The parameters between two occasions were compared using the Wilcoxon signed-rank test. Results. After peppermint oil intake, the T lag and beta constant were significantly decreased. No significant differences in T 1/2, GEC, or kappa were observed between the two occasions. Conclusions. The decrease in the T lag and beta constant suggests acceleration of gastric emptying during the early phase. This study showed that peppermint oil enhances gastric emptying, suggesting the potential use of peppermint oil in clinical settings for patients with functional gastrointestinal disorders.

DOI： 10.1007/s00535-007-2067-3

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記述言語：英語   出版者・発行元：SPRINGER TOKYO  

DOI： 10.1007/s00535-007-2024-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER TOKYO  

Background. The changes in nonalcoholic fatty liver disease range over a wide spectrum, extending, from simple steatosis to nonalcoholic steatohepatitis (NASH). We investigated the clinical usefulness of the type IV collagen 7s domain and hyaluronic acid for predicting the severity of fibrosis before progression to the cirrhotic stage in NASH patients. Methods. The type IV collagen 7s domain and hyaluronic acid were measured in 72 patients with histologically verified NASH. Results. In a univariate analysis, marked elevation of hyaluronic acid and the type IV collagen 7s domain was observed in the NASH patients with advanced fibrosis compared with those with mild fibrosis (P = 0.0028, P = 0.0006, respectively). For detection of NASH with advanced fibrosis, the area under the receiver-operating characteristic curves for type IV collagen 7s domain and hyaluronic acid were 0.767 and 0.754, respectively. However, multiple regression analysis revealed that the type IV collagen 7s domain, but not hyaluronic acid, was significantly elevated in patients with advanced fibrosis even after adjustment for age, sex, platelet count, prothrombin time, aspartate aminotransferase/alanine aminotransferase ratio, body mass index, and presence of underlying type 2 diabetes mellitus, all of which have previously been reported as useful predictors of advanced fibrosis in patients with NASH (P = 0.0127, P = 0.2804, respectively). Conclusions. This is the first report to demonstrate a consistent and profound elevation of the type IV collagen 7s domain in NASH patients with advanced fibrosis (before progression to the stage of cirrhosis) compared with those with mild fibrosis.

DOI： 10.1007/s00535-007-2014-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BLACKWELL PUBLISHING  

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury. The spectrum of NAFLD is broad, extending from simple steatosis through nonalcoholic steatohepatitis (NASH). Insulin resistance has been found to increase the risk of NASH, and obesity, and decreased levels of adiponectin are important factors in determining the severity of insulin resistance. Recent evidence has indicated that hypoadiponectinemia is involved in hepatic steatosis and NASH.
Methods: To investigate whether hypoadiponectinemia causes hepatic steatosis in type 2 diabetes mellitus (DM) patients independently of visceral adipose tissue, we measured the plasma adiponectin concentration, hepatic fat content based on the liver-to-spleen ratio (L/S ratio) according to computed tomography (CT) attenuation values, and the amount of visceral adipose tissue and subcutaneous adipose tissue by CT in 248 type 2 DM patients. We also investigated the relationship between the serum level of adiponectin and hepatic fibrosis.
Results: Significant correlations were observed between the L/S ratios and aspartate aminotransferase, alanine aminotransferase, visceral adipose tissue, subcutaneous adipose tissue, and serum adiponectin values (r=0.300, p=0.0007), and there was a highly significant inverse correlation between the visceral adipose tissue values and the serum adiponectin levels (r=-0.327, p < 0.0002). The subcutaneous adipose tissue values, however, were not correlated with the serum adiponectin levels. Multiple regression analysis was used to quantify the impact of measured variables on the L/S ratio. After adjustment for age, gender, and visceral adipose tissue, the serum adiponectin levels were still significantly correlated with the L/S ratios (p=0.0064). And there was a stepwise decrease in the serum adiponectin in parallel to the severity of hepatic fibrosis.
Conclusions: Hypoadiponectinemia is concluded to be involved in the etiology of hepatic steatosis independently of visceral adipose tissue content, and is considered to be an important factor in the progression of fibrosis; further studies will be necessary to elucidate the exact physiological role of adiponectin and its contribution to the progression of NASH.

DOI： 10.1111/j.1530-0277.2006.00281.x

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000102965

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000102964

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DOI： 10.1159/000102966

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DOI： 10.1159/000106753

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DOI： 10.1159/000104729

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DOI： 10.1159/000106754

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000108627

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106975

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106777

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000107937

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000106976

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記述言語：英語   出版者・発行元：KARGER  

DOI： 10.1159/000100968

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER DIABETES ASSOC  

OBJECTIVE - Until now, few clinical studies have reported on the association between the indexes of body fat distribution and serum ferritin, an indicator of body iron stores and a putative risk factor for insulin resistance. We investigated the association between serum ferritin concentrations and the indexes of distribution of adipose tissues in the body, such as the visceral fat area (VFA), the subcutaneous fat area (SFA), and the hepatic fat content in Japanese subjects.
RESEARCH DESIGN AND METHODS - A total of 248 Japanese subjects (127 men and 121 postmenopausal. women aged 57.8 +/- 13.9 years, BMI 25.7 +/- 4.6 kg/m(2); 1.40 subjects with type 2 diabetes and 108 nondiabetic subjects) were evaluated. Subjects with a history of alcohol intake were exicluded from the study. We measured body height, body weight, and serum ferritin, as well as lasting plasma glucose and plasma insulin concentrations. We estimated insulin resistance by homeostasis model assessment. The fat distribution was evaluated by measuring the VFA and SFA by abdominal computed tomography at the umbilical level. To assess the hepatic fat content, the ratio of the computed tomography attenuation value of the liver to that of the spleen was calculated.
RESULTS - Serum ferritin was significantly correlated with the various indexes of adiposity examined, such as the hepatic fat content (r = -0.280, P < 0.0001), VFA (r = 0.254, P < 0.0001, SFA (r = 0..231, P - 0.0005), and homeostasis model assessment (r = 0.286, P 0.0008).
CONCLUSIONS - This is the first report to directly demonstrate an association between serum ferritin and VFA and SFA. The results of this study suggest that the serum ferritin concentration may be a useful indicator of systemic fat content and degree of insulin resistance.

DOI： 10.2337/diacare.28.10.2486

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