Hita, Japan
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Nakano T.,Chang Gung Memorial Hospital Kaohsiung Medical Center | Nakano T.,Chang Gung University | Cheng Y.-F.,Chang Gung Memorial Hospital | Lai C.-Y.,Chang Gung Memorial Hospital Kaohsiung Medical Center | And 14 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Non-alcoholic steatohepatitis (NASH) is recognized as the most severe form of non-alcoholic fatty liver disease, with likely progression to liver cirrhosis and hepatocellular carcinoma. However, there is no unified standard for diagnosis and therapeutics. This study aimed to characterize lipid transfer/metabolic proteins as non-invasive diagnostic markers, and to evaluate the therapeutic effects of phototherapy on the progression of NASH in rats. Methods: Lewis rats given a choline-deficient and iron-supplemented l-amino acid-defined (CDAA) diet and Zucker fa/fa rats were used as a diet-induced and an obesity-related NASH models, respectively, with or without phototherapy. Results: Serum apolipoprotein E and low molecular weight-adiponectin levels were gradually reduced and reached the lowest level at fatty liver/NASH stage both in CDAA diet-induced NASH model and in genetically obese model. Total-adiponectin levels were dramatically elevated after NASH was established in CDAA diet-induced NASH model. Phototherapy ameliorated hepatocyte apoptosis, inflammation, fibrosis, and insulin/leptin resistance caused by CDAA diet with alteration of the levels of lipid transfer/metabolic proteins and elevation of the circulating active form of vitamin D 3. Vitamin D 3 supplementation ameliorated NASH progression in CDAA diet-induced NASH model. However, phototherapy failed to ameliorate the obesity and steatosis, suggesting that phototherapy may possess anti-inflammatory/fibrotic activity rather than anti-obesity/steatotic activity. Conclusions: These results suggest that serum lipid transfer/metabolic proteins and vitamin D 3 status may be effective biomarkers for non-invasive diagnosis of NASH progression, and that phototherapy may be a good complementary therapy for NASH because of its regulation of lipid transfer/metabolic proteins and vitamin D 3. © 2010 European Association for the Study of the Liver.


Nakano T.,Chang Gung University | Nakano T.,Kaohsiung Chang Gung Memorial Hospital | Chen C.-L.,Kaohsiung Chang Gung Memorial Hospital | Goto S.,Kaohsiung Chang Gung Memorial Hospital | Goto S.,Iwao Hospital
Clinical and Developmental Immunology | Year: 2013

In addition to cellular immune responses, humoral immune responses, mediated by natural antibodies, autoantibodies, and alloantibodies, have increasingly been recognized as causes of organ transplant rejection. In our previous studies, we have demonstrated the induction of antinuclear antibodies against histone H1 and high-mobility group box 1 (HMGB1), in both experimental and clinical liver transplant tolerance. The active induction of antinuclear antibodies is usually an undesirable phenomenon, but it is often observed after liver transplantation. However, the release of nuclear antigens and its suppression by neutralizing antibodies are proposed to be important in the initiation and regulation of immune responses. In this review article, we summarize the current understanding of nuclear antigens and corresponding antinuclear regulatory antibodies (Abregs) on infection, injury, inflammation, transplant rejection, and tolerance induction and discuss the significance of nuclear antigens as diagnostic and therapeutic targets. © 2013 Toshiaki Nakano et al.


Takaoka Y.,Kaohsiung Chang Gung Memorial Hospital | Takaoka Y.,Hiroshima University | Goto S.,Kaohsiung Chang Gung Memorial Hospital | Goto S.,Iwao Hospital | And 10 more authors.
Scientific Reports | Year: 2014

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an energy metabolism-related enzyme in the glycolytic pathway. Recently, it has been reported that GAPDH has other physiological functions, such as apoptosis, DNA repair and autophagy. Some in vitro studies have indicated immunological aspects of GAPDH function, although there is no definite study discussing the advantage of GAPDH as a therapeutic target. Here, we show that GAPDH has an anti-inflammatory function by using a lipopolysaccharide (LPS)-induced, sepsis-related severe acute lung injury (ALI) mouse model, which is referred to as acute respiratory distress syndrome (ARDS) in humans. GAPDH pre-injected mice were protected from septic death, and their serum levels of proinflammatory cytokines were significantly suppressed. In lung tissue, LPS-induced acute injury and neutrophil accumulation were strongly inhibited by GAPDH pre-injection. Pulmonary, proinflammatory cytokine gene expression and serum chemokine expression in GAPDH pre-injected mice were also reduced. These data suggest the therapeutic potential of GAPDH for sepsis-related ALI/ARDS.


Tanaka M.,Yokokura Hospital | Ando E.,Iwao Hospital | Simose S.,Kurume University | Hori M.,Kurume University | And 5 more authors.
Hepatology Research | Year: 2014

Aim: Radiofrequency ablation therapy (RFA) combined with transarterial chemoembolization (TACE) (combination therapy) is effective for early-stage hepatocellular carcinoma (HCC). The aim of this study was to compare the long-term effects of combination therapy with supportive care alone for intermediate HCC. Methods: The study included 58 patients with intermediate HCC who received combination therapy (n=34) or supportive care alone (n=24). The inclusion criteria were a single nodule of more than 50mm in diameter or two to three nodules, each measuring more than 30mm in diameter, or more than three nodules, no vascular invasion and no extrahepatic metastasis. Results: The overall survival rates at 1, 2, 3 and 5 years of the combination therapy group (91%, 65%, 53% and 27%, respectively) were significantly better (P<0.0001) than those of the supportive care group (42%, 8%, 8% and 0%, respectively). Multivariate analysis identified treatment modality (combination therapy vs supportive care alone: P<0.0001, risk ratio [RR]=4.290 [95% confidence interval [CI]=2.157-8.529]) and serum α-fetoprotein (P=0.017, RR=2.318 [95% CI=1.166-4.610]) as independent and significant factors of overall survival. Conclusion: The combination of TACE and RFA is a safe and effective therapy in patients with intermediate HCC. © 2013 The Japan Society of Hepatology.


Iwao T.,Iwao Hospital | Sakai K.,Iwao Hospital | Sata M.,Kurume University
Journal of Diabetes and its Complications | Year: 2013

Aims: Liraglutide improves glycemic control in patients with type 2 diabetes. However, no information is available about an indicator of successful switching to liraglutide monotherapy from complex insulin therapy in Japanese patients with type 2 diabetes. Methods: We studied 69 patients with type 2 diabetes, including 39 consecutive successful patients and 30 consecutive unsuccessful patients from insulin therapy to liraglutide monotherapy. Before switching, we measured urinary C-peptide, fasting C-peptide and postprandial C-peptide at 30, 60 and 120 min loading a test meal. In successful patients, HbA1c and body weight were measured at 4, 8, and 12 weeks after switching. Results: Using univariate analysis, duration of disease was significantly higher in unsuccessful patients than in successful patients. Urinary C-peptide, fasting C-peptide, and postprandial C-peptides were significantly higher in successful patients than in unsuccessful patients. Multiple logistic regression analysis showed that postprandial C-peptide at 60 min was an independent predictor of successful switching to liraglutide monotherapy from insulin therapy (odds ratio, 7.28; 95% confidence interval, 2.89-18.36). In the receiver operating characteristic analyses, 2.9 ng/mL of postprandial C-peptide at 60 min was the best cut-off value, providing that sensitivity and specificity were 95% and 93%, respectively. In the follow-up period, successful patients showed a sustained reduction in HbA1c and body weight without hypoglycemia. Conclusions: Postprandial C-peptide at 60 min is a useful parameter in the prediction of successful switching from insulin therapy to liraglutide monotherapy in Japanese patients with type 2 diabetes. © 2013 Elsevier Inc.


Iwao T.,Iwao Hospital | Sakai K.,Iwao Hospital | Ando E.,Iwao Hospital
Journal of Diabetes Investigation | Year: 2013

Aims/Introduction: To identify upper limit post-load 1-h plasma glucose (1-h PG) after 75-g oral glucose test in a Japanese population. Materials and Methods: A total of 918 subjects were enrolled. We divided the subjects into two groups: normal 2-h post-load plasma glucose (2-h PG; <140 mg/dL) and impaired 2-h PG group (≥140 mg/dL). Results: A total of 417 subjects had normal 2-h PG and 501 had impaired 2-h PG. The receiver operating characteristic (ROC) curve showed that the optimal cut-off value of 1-h PG was 179 mg/dL (area under ROC curve = 0.89), providing that the sensitivity, specificity, and positive and negative predictive value were 85, 79, 82 and 83%, respectively. The subjects with 1-h PG < 179 mg/dL consisted of 0.5% diabetes and 99.5% non-diabetes, whereas those with 1-h PG ≥ 179 mg/dL consisted of 26.9% diabetes and 73.1% non-diabetes (P < 0.01). Furthermore, there was a significant correlation between 1-h PG and 2-h PG (r2 = 0.57, P < 0.01). Conclusions: These data suggested that 179 mg/dL is the upper limit of the normal range of post-load of 1-h PG in a Japanese population. Thus, the subjects with 1-h PG ≥ 179 mg/dL might be at risk of developing future diabetes. Therefore, appropriate prospective study should be carried out to test this hypothesis. © 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd.


Iwao T.,Iwao Hospital | Sakai K.,Iwao Hospital | Ando E.,Iwao Hospital
Diabetology International | Year: 2013

Aims: We examined whether diet and/or physical activity contribute to seasonal variation of hemaglobin A1c (HbA1c) in Japanese diabetic patients. Materials and methods: We studied 207 patients from 2009 to 2010. HbA1c measurements, clinical parameters, and practices of diet and physical activities were assessed. For the time-series analysis, each patient was classified as complete, incomplete, or no fluctuation. Results: Patients showed a clear seasonal fluctuation of HbA1c levels (P < 0.01), with the highest levels being in March (7.19 %) and the lowest in October (6.87 %). The time-series analysis showed that 123 patients had complete or incomplete fluctuation. Of them, 107 exhibited normal fluctuation and only 16 had reverse fluctuation. In the former, both HbA1c levels and body weight were higher in winter/spring than in summer/autumn (7.3 vs. 6.9 %, P < 0.01; 59.8 vs. 59.2 kg, P < 0.01). In the latter, both HbA1c and body weight were lower in winter/spring than in summer/autumn (7.2 vs. 7.5 %, P < 0.01; 59.8 vs. 60.1 kg, P < 0.01). In patients with normal fluctuation, dietary practice remained steady across seasons, but physical activity was less in winter/spring than in summer/autumn (22 vs. 35 %, P < 0.05). Conclusions: Seasonal fluctuations in HbA1c levels are observed in most Japanese diabetic patients. Our questionnaire may indicate that reduced self-reported physical activity is a potential factor affecting seasonal fluctuations in HbA1c levels. © 2013 The Japan Diabetes Society.


Iwao T.,Iwao Hospital | Sakai K.,Iwao Hospital | Ando E.,Iwao Hospital
Diabetes Research and Clinical Practice | Year: 2013

Aims: There are conflicting interpretations regarding the normal fasting plasma glucose level in Japanese subjects. We therefore aimed to define the upper limit of fasting plasma glucose level. Methods: A total of 962 subjects who had a 75-g oral glucose tolerance test were examined. Subjects were divided into two groups - post-load normal glycemic group (2-h plasma glucose <140. mg/dL) and post-load hyperglycemic group (2-h plasma glucose ≥ 140. mg/dL). Results: There were 434 subjects with post-load normal glycemia and 528 subjects with post-load hyperglycemia. Receiver operating characteristic curve (ROC) demonstrated that the optimal cut-off value for predicting post-load hyperglycemia was a fasting plasma glucose of 99. mg/dL (area under ROC curve = 0.81), which had a sensitivity, specificity, and overall diagnostic accuracy of 68%, 81%, 74%, respectively. Conclusions: These data suggest that for predicting post-load hyperglycemia, the optimal cut-off value of fasting plasma glucose was 99. mg/dL in Japanese subjects. Thus, the current cut-off value of fasting plasma glucose of 110. mg/dL in Japan might be lowered. © 2013 Elsevier Ireland Ltd.


Iwao T.,Iwao Hospital | Sakai K.,Iwao Hospital | Ando E.,Iwao Hospital
Internal Medicine | Year: 2014

Objective We examined the relative contribution of insulin secretion and insulin sensitivity at different stages of glucose tolerance in non-obese and obese Japanese subjects. Methods A total of 641 subjects who underwent 75-g glucose tolerance testing were divided into two groups: 436 non-obese subjects (body mass index: BMI <25) and 205 obese subjects (BMI ≥ 25). The subjects were further divided into four groups: those with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes. We compared insulin secretion and sensitivity indices, such as the insulinogenic index (IGI), homeostatic model insulin resistance (HOMA-IR), homeostatic model assessment of β-cell (HOMA-β) and insulin sensitivity index (ISI). Results In a univariate analysis, the obese subjects had higher levels of HOMA-IR, HOMA-β and IGI associated with lower ISI values in comparison with that observed in the non-obese subjects at different stages of glucose tolerance. A multiple logistic regression analysis showed that the HOMA-IR was a significant independent factor between the non-obese and obese subjects; the odds ratio (OR) (95% confidential interval: CI) was 3.78 (2.04-7.01; p<0.01) in the NGT group, 4.91 (2.06-11.72; p<0.01) in the IGT group and 2.02 (1.22- 3.34; p<0.01) in the diabetes group. Although a similar trend was also observed in the IFG group (OR= 15.83), the difference did not reach a level of statistical significance (p=0.066). Conclusion These data suggest that obese subjects are characterized by increased insulin resistance rather than reduced insulin secretion at all stages of glucose tolerance. Therefore, non-obese subjects and obese subjects are distinct entities at all stages of glucose tolerance. © 2014 The Japanese Society of Internal Medicine.


PubMed | Iwao Hospital
Type: Journal Article | Journal: Internal medicine (Tokyo, Japan) | Year: 2014

We examined the relative contribution of insulin secretion and insulin sensitivity at different stages of glucose tolerance in non-obese and obese Japanese subjects.A total of 641 subjects who underwent 75-g glucose tolerance testing were divided into two groups: 436 non-obese subjects (body mass index: BMI <25) and 205 obese subjects (BMI 25). The subjects were further divided into four groups: those with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and diabetes. We compared insulin secretion and sensitivity indices, such as the insulinogenic index (IGI), homeostatic model insulin resistance (HOMA-IR), homeostatic model assessment of -cell (HOMA-) and insulin sensitivity index (ISI).In a univariate analysis, the obese subjects had higher levels of HOMA-IR, HOMA- and IGI associated with lower ISI values in comparison with that observed in the non-obese subjects at different stages of glucose tolerance. A multiple logistic regression analysis showed that the HOMA-IR was a significant independent factor between the non-obese and obese subjects; the odds ratio (OR) (95% confidential interval: CI) was 3.78 (2.04-7.01; p<0.01) in the NGT group, 4.91 (2.06-11.72; p<0.01) in the IGT group and 2.02 (1.22-3.34; p<0.01) in the diabetes group. Although a similar trend was also observed in the IFG group (OR=15.83), the difference did not reach a level of statistical significance (p=0.066).These data suggest that obese subjects are characterized by increased insulin resistance rather than reduced insulin secretion at all stages of glucose tolerance. Therefore, non-obese subjects and obese subjects are distinct entities at all stages of glucose tolerance.

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