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IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Aims/Introduction No reports have been published on the association between dietary intake habits and nocturia in the diabetes population. We therefore evaluated this issue among Japanese patients with diabetes mellitus. Materials and Methods Study participants in the present study were 785 Japanese patients with type 2 diabetes mellitus. Self-administered questionnaires were used to assess each type of dietary intake habit. Vegetable intake habit was assessed by the following question: “Do you have vegetables or seaweed every day?” We used the following two outcomes: (i) nocturia: ≥2 voids per night; and (ii) severe nocturia: ≥3 voids per night. Adjustment was made for age, sex, body mass index, glycated hemoglobin, hypertension, dyslipidemia, smoking, drinking, exercise habit, stroke, ischemic artery disease, diabetic nephropathy, diabetic neuropathy and diabetic retinopathy. Results The prevalence of nocturia, severe nocturia, and vegetable intake habit was 39.9%, 14.4% and 67.3%, respectively. After adjusting for confounding factors, vegetable intake habit was independently inversely associated with nocturia and severe nocturia: the adjusted odds ratios were 0.67 (95% confidence interval [CI] 0.48–0.94) and 0.46 (95% CI 0.30–0.71), respectively. Among male patients, vegetable intake habit was independently inversely associated with severe nocturia, but not nocturia: the adjusted OR was 0.51 (95% CI 0.29–0.88). Among female patients, vegetable intake habit was independently inversely associated with nocturia and severe nocturia: the adjusted ORs were 0.44 (95% CI 0.24–0.79) and 0.34 (95% CI 0.15–0.78), respectively. Conclusions We found an inverse association between vegetable intake habit and nocturia in Japanese patients with type 2 diabetes mellitus.

Aim Nocturia is common among patients with type 2 diabetes mellitus, but limited evidence regarding the association between body mass index (BMI) and nocturia exists among such patients. The aim of the present study, therefore, was to evaluate the association between BMI and nocturia among Japanese patients with type 2 diabetes mellitus. Methods Study participants were 809 Japanese patients with type 2 diabetes mellitus. Study participants were considered to have nocturia if they answered “two or more” to the question: “How many times do you typically wake up to urinate from sleeping at night until waking in the morning?” We used the following two outcomes: (i) moderate nocturia was defined as ≥2 voids per night; and (ii) severe nocturia was defined as ≥3 voids per night. Participants were categorized into four groups according to their BMI: (i) BMI

Aims/Introduction To date, there is no evidence regarding the association between physical activity (PA) and erectile dysfunction (ED) among Japanese patients with type 2 diabetes mellitus. We investigated this issue among Japanese patients with type 2 diabetes mellitus. Materials and Methods Study participants were 460 male Japanese patients with type 2 diabetes mellitus. The definitions of exercise habit, walking habit and fast walking were based on a self-administered questionnaire regarding PA behavior. Participants were classified into one of four PA levels based on the number of ‘Yes’ answers to the three questions in the questionnaire: (i) lowest; (ii) lower; (iii) moderate; and (iv) higher. Severe ED and moderate-to-severe ED were based on Sexual Health Inventory for Men score

Objective Macrovascular diseases and urgency incontinence are common among Japanese patients with type 2 diabetes mellitus. However, little evidence exists regarding the association between stroke and urgency incontinence among patients with type 2 diabetes mellitus. We examined the associations between macrovascular complications and urgency incontinence among Japanese patients with type 2 diabetes mellitus. Methods The study subjects were 818 Japanese patients with type 2 diabetes mellitus. Urgency incontinence was defined as present when a subject answered "once a week or more" to the question: "Within one week, how often do you leak urine because you cannot defer the sudden desire to urinate?" We adjusted our analyses for sex, age, body mass index, duration of type 2 diabetes, current smoking, current drinking, hypertension, dyslipidemia, glycated hemoglobin, diabetic nephropathy, diabetic retinopathy, and diabetic peripheral neuropathy. Results The prevalence of urgency incontinence was 9.2%. Stroke was independently positively associated with urgency incontinence, with an adjusted odds ratio of 2.34 (95% confidence interval: 1.03-4.95). The associations between ischemic heart disease or peripheral artery disease and the prevalence of urgency incontinence were not significant. Conclusion In Japanese patients with type 2 diabetes mellitus, stroke, but not ischemic heart diseases or peripheral artery disease, was independently positively associated with urgency incontinence.

Only limited epidemiological evidence exists regarding the relationship between diabetic neuropathy and erectile dysfunction (ED) among Japanese patients with type 2 diabetes mellitus. To investigate the relationship between diabetic neuropathy and ED among Japanese patients with type 2 diabetes mellitus, a multicenter cross-sectional study was conducted in 287 male Japanese patients with type 2 diabetes mellitus, age (19-65 years). Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms, decreased or disappeared Achilles tendon reflex and/or abnormal vibration perception. ED, moderate to severe ED, and severe ED were defined as present when a subject had a Sexual Health Inventory for Men score

AIMS No evidence exists regarding the association between smoking status and nocturia among patients with type 2 diabetes mellitus. We evaluated this association among Japanese patients with type 2 diabetes mellitus by post-hoc analysis. METHODS Study subjects were 817 Japanese patients with type 2 diabetes mellitus. Study subjects were considered to have nocturia if they answered “once or more” to the question: “Within one week, how many times do you typically wake up to urinate from sleeping at night until waking in the morning?” We used the following three outcomes: (1) nocturia was ≥1 voids per night; (2) moderate nocturia was ≥2 voids per night; and (3) severe nocturia was ≥3 voids per night. Adjustments were made for age, sex, body mass index, hypertension, dyslipidemia, stroke, glycated hemoglobin, current drinking, use of anti-hypertensive agent, use of insulin, use of oral anti-hyperglycemic agent, and diabetic retinopathy. RESULTS The prevalence values of one void per night, two voids per night, and three or more voids per night were 39.5%, 27.1%, and 14.8%, respectively. Current smoking was independently inversely associated with severe nocturia compared with never or former smoking; the adjusted PR was 0.47 (95%CI: 0.25–0.89). Among the 443 patients who had ever smoked, compared with former smoking, current smoking was independently inversely related to severe nocturia; the adjusted PR was 0.44 (95%CI: 0.24–0.82). CONCLUSIONS In Japanese patients with type 2 diabetes mellitus, current smoking may be independently inversely associated with severe nocturia.

Aims We aimed to evaluate the association between serum lipoprotein(a) [Lp(a)] levels and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. Methods This study included 581 patients with type 2 diabetes mellitus. Serum Lp(a) levels were divided into four groups; the cut-off points were at the 30th, 60th, and 90th percentile values on the basis of the distribution for all subjects. Diabetic nephropathy was defined as present when the urinary albumin-creatinine ratio was ≥33.9mg/mmol creatinine and/or the estimated glomerular filtration rate was 2 . Adjustment was made for age, sex, body mass index, hemoglobin A 1c , duration of diabetes mellitus, current drinking, current smoking, hypertension, dyslipidemia, coronary heart disease, and stroke. Results Higher serum Lp(a) levels were significantly associated with a higher prevalence of diabetic nephropathy: the adjusted odds ratios (95% confidence intervals) for diabetic nephropathy in relation to serum Lp(a) levels of ≤6, 7–15, 16–38, and ≥39mg/dl were 1.00 (reference), 2.74 (1.08–7.00), 3.31 (1.28–8.54), and 4.80 (1.57–14.60), respectively ( P for trend=0.004). Conclusions The results suggest that serum Lp(a) levels may be positively associated with diabetic nephropathy among Japanese patients with type 2 diabetes mellitus.

Aims Diabetes was significantly positively associated with urgency incontinence in several epidemiological studies. We examine the association between diabetic neuropathy, which we defined based on neuropathic symptoms, the absence of the Achilles reflex, and/or abnormal vibration perception, and urgency incontinence among Japanese patients with type 2 diabetes mellitus. Methods Study subjects were 742 Japanese patients with type 2 diabetes mellitus, aged 19–70 years, who had undergone blood tests at our institutions. A self-administered questionnaire was used to collect information on the variables under study. Urgency incontinence was defined as present when a subject answered “once a week or more” to the question: “Within one week, how often do you leak urine because you cannot defer the sudden desire to urinate ?”. Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms, the absence of the Achilles reflex, and/or abnormal vibration perception. Adjustment was made for sex, age, body mass index, duration of type 2 diabetes mellitus, current smoking, hypertension, dyslipidemia, glycated hemoglobin, stroke, coronary artery disease, insulin therapy, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Results The prevalence of urgency incontinence was 8.6%. Diabetic neuropathy was independently positively associated with urgency incontinence: the adjusted OR was 2.20 (95%CI: 1.16–4.36). Associations between diabetic retinopathy or nephropathy and the prevalence of urgency incontinence were not significant. Conclusions In Japanese patients with type 2 diabetes mellitus, only diabetic neuropathy was independently positively associated with urgency incontinence. Neurourol. Urodynam. © 2015 Wiley Periodicals, Inc.

Among patients with type 2 diabetes mellitus, the association between B-type natriuretic peptide (BNP) and renal function remains controversial. We therefore investigated this issue among Japanese patients with type 2 diabetes mellitus. This study included 687 Japanese patients with type 2 diabetes mellitus. BNP levels were divided at quartile points on the basis of the distribution. We used four outcomes regarding the renal function: 1) chronic kidney disease (CKD): estimated glomerular filtration rate (eGFR) < 60ml/min/1.72m2, 2) advanced CKD: eGFR < 30ml/min/1.72m2, 3) microalbuminuria: urinary albumin creatinine ratio (UACR) ≥ 30 mg/g creatinine, and 4) macroalbuminuria: UACR ≥ 300 mg/g creatinine. The prevalence values of CKD, advanced CKD, microalbuminuria, and macroalbuminuria were 27.4％, 2.5%, 31.4%, and 9.3%, respectively. Highest BNP (≥ 39.2 ng/ml) was independently positively associated with microalbuminuria and macroalbuminuria (adjusted ORs, 2.61 [95% CI: 1.53-4.49] and 3.45 [95% CI: 1.46-8.72], respectively). High BNP was not associated with advanced CKD or CKD. There was a statistically significant positive exposure-response relationships between the BNP level and advanced CKD, microalbuminuria, and macroalbuminuria (p for trend = 0.047, 0.001, and 0.003, respectively). BNP level may be independently positively associated with advanced CKD, microalbuminuria, and macroalbuminuria but not CKD in Japanese patients with type 2 diabetes mellitus.

Nocturia is common among patients with type 2 diabetes mellitus, but limited evidence regarding the association between body mass index (BMI) and nocturia exists among such patients. The aim of the present study, therefore, was to evaluate the association between BMI and nocturia among Japanese patients with type 2 diabetes mellitus.Study participants were 809 Japanese patients with type 2 diabetes mellitus. Study participants were considered to have nocturia if they answered "two or more" to the question: "How many times do you typically wake up to urinate from sleeping at night until waking in the morning?" We used the following two outcomes: (i) moderate nocturia was defined as ≥2 voids per night; and (ii) severe nocturia was defined as ≥3 voids per night. Participants were categorized into four groups according to their BMI: (i) BMI18.5; (ii) 18.5 ≤ BMI 25; (iii) 25 ≤ BMI 30; and (iv) BMI ≥30. Multiple logistical regression analysis for nocturia in relation to BMI was used, with the category of 18.5 ≤ BMI 25 as the reference.Obesity (BMI ≥30) was independently positively associated with severe nocturia among elderly patients (age ≥65 years) with type 2 diabetes mellitus, but not among young and middle-aged patients: the adjusted OR was 2.96 (95% CI 1.10-7.83). BMI was not associated with moderate nocturia in all patients.In Japanese elderly patients with type 2 diabetes mellitus, obesity was independently positively associated with severe nocturia. Geriatr Gerontol Int 2017; 17: 2460-2465.

Objectives No studies have investigated the association between nocturia and depressive symptoms in patients with type 2 diabetes mellitus. Because nocturia and depressive symptoms are common in patients with type 2 diabetes, we examined this association in Japanese patients with type 2 diabetes. Methods We studied 762 Japanese patients with type 2 diabetes. A self-administered questionnaire was used to collect information about the variables under study. The subjects were divided into 3 groups according to their nocturnal micturition: 1) no nocturia; 2) mild nocturia (1 void per night) and 3) moderate to severe nocturia (2 or more voids per night). Depressive symptoms were defined as being present when a subject had a Self-Rating Depression Scale score higher than 49. Results The prevalence values of mild nocturia, moderate to severe nocturia and depressive symptoms were 39.5%, 41.9% and 16.8%, respectively. Both mild nocturia and moderate to severe nocturia were independently positively associated with depressive symptoms in all patients; the adjusted ORs were 1.96 (95% CI 1.06 to 3.77) and 2.58 (95% CI 1.38 to 5.04). In female patients, both mild nocturia and moderate to severe nocturia were independently associated with depressive symptoms; the adjusted ORs were 5.26 (95% CI 1.73 to 20.61) and 6.91 (95% CI 2.15 to 28.54), respectively. In male patients, neither mild nocturia nor moderate to severe nocturia was significantly related to depressive symptoms. Conclusions In Japanese female patients with type 2 diabetes, nocturia may be positively associated with depressive symptoms.

The clinical features of fatty liver (FL) detected by ultrasonography (US) in nonobese and diabetes mellitus type 2 are not yet understood, and metabolic syndrome (MetS) has become an important health issue throughout the world. We investigated the clinical features of fatty liver (FL) in nonobese patients. From 2008 to 2010, 2192 Japanese patients underwent a medical checkup at our hospital. Obesity was defined as a body mass index (BMI) ≥25 kg/m2, while normal waist circumference (WC) was defined as

No evidence exists regarding the association between sitting time and erectile dysfunction (ED) among patients with type 2 diabetes mellitus. The aim of this study was to evaluate the association between self-reported sitting time and ED among patients with type 2 diabetes mellitus.Study subjects were 430 male Japanese patients with type 2 diabetes mellitus (mean age, 60.5years). A self-administered questionnaire was used to collect information on the variables under study. The study subjects were asked about time spent sitting during typical 24-hour periods over the past 12months. Subjects were divided into four groups according to self-reported sitting time: 1)5hours, 2) 5-7hours, 3) 7-9hours, and 4) ≥9hours. ED was defined as present when a subject had a Sexual Health Inventory for Men score8. Adjustment was made for age, body mass index, duration of type 2 diabetes, current smoking, current drinking, hypertension, coronary artery disease, stroke, glycated hemoglobin, walking habit, and diabetic neuropathy.The prevalence values of moderate to severe ED and severe ED were 36.1% and 49.8%. At least 9hours sitting was independently positively associated with severe ED but not moderate to severe ED; the adjusted OR was 1.84 (95% CI: 1.06-3.33). In the multivariate model, there was a statistically significant inverse exposure-response relationship between the self-reported sitting time and severe ED (p for trend=0.029).Self-reported sitting time may be positively associated with ED in Japanese patients with type 2 diabetes mellitus.

In several studies of patients with type 2 diabetes mellitus, a positive association between depressive symptoms and erectile dysfunction (ED) has been reported. No evidence exists, however, regarding the association between depressive symptoms and ED among Japanese patients with type 2 diabetes mellitus. Thus, we examined this issue among Japanese patients with type 2 diabetes mellitus. Study subjects were 469 male Japanese patients with type 2 diabetes mellitus, aged 19 years or over. ED, moderate to severe ED and severe ED were defined as present when a subject had a Sexual Health Inventory for Men score22,12 and8, respectively. Depressive symptoms were defined as present when a subject had a Self-Rating Depression Scale (SDS) score49. Adjustment was made for age, body mass index, waist, duration of type 2 diabetes, current smoking, current drinking, hypertension, dyslipidemia, coronary artery disease, stroke, glycated hemoglobin and diabetic neuropathy. The prevalence values of depressive symptoms, moderate to severe ED and severe ED were 15.1%, 64.2% and 51.0%, respectively. Depressive symptoms were independently positively associated with moderate to severe ED and severe ED (adjusted odds ratios were 2.23 (95% confidence interval (CI): 1.17-4.43) and 1.86 (95% CI: 1.04-3.41), respectively). In Japanese patients with type 2 diabetes mellitus, depressive symptoms may be associated with ED.

Objective To evaluate the association between microvascular complications and nocturia among Japanese patients with type 2 diabetes mellitus. Methods Study subjects were 731 Japanese patients with type 2 diabetes mellitus. A self-administered questionnaire was used to collect information on the variables under study. Study subjects were considered to have nocturia if they answered " once or more " to the question: "How many times do you typically wake up to urinate from sleeping at night until waking in the morning?" Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms, the absence of the Achilles reflex, or abnormal vibration perception. Diabetic nephropathy was defined as positive when the estimated glomerular filtration rate was 2 and/or the urine albumin-to-creatinine ratio was ≥34 mg/mmol creatinine. Several ophthalmology specialists were responsible for evaluating diabetic retinopathy. Adjustment was made for sex, age, body mass index, duration of diabetes mellitus, current smoking, current drinking, hypertension, stroke, ischemic heart disease, and glycated hemoglobin. Results The prevalence of nocturia was 80.4%. Diabetic retinopathy was independently positively associated with nocturia (adjusted odds ratio 2.39 [95% confidence interval: 1.08-6.11]). In contrast, diabetic nephropathy or diabetic neuropathy was not associated with nocturia. Conclusion In Japanese patients with type 2 diabetes mellitus, only diabetic retinopathy was independently positively associated with nocturia.

Aims/Introduction Several epidemiological studies have reported a positive association between nocturia and erectile dysfunction (ED). Yet only limited evidence exists regarding the association between nocturia and ED among patients with type 2 diabetes mellitus, although nocturia and ED are common among type 2 diabetes mellitus patients. Material and Methods Study participants were 332 male Japanese patients with type 2 diabetes mellitus, aged 19–70 years, who had undergone blood tests at our institutions. A self‐administered questionnaire was used to collect information on the variables under study. Adjustment was made for age, body mass index, hypertension, stroke, ischemic heart disease, glycated hemoglobin and diabetic neuropathy. ED, moderate to severe ED and severe ED were defined as present when a participant had a Sexual Health Inventory for Men score, Several epidemiological studies have reported a positive association between nocturia and erectile dysfunction (ED). Yet only limited evidence exists regarding the association between nocturia and ED among patients with type 2 diabetes mellitus, although nocturia and ED are common among type 2 diabetes mellitus patients.

Diabetes mellitus and heavy alcohol consumption are both associated with vascular disease, a category that includes erectile dysfunction (ED). However, the association between alcohol consumption and ED among patients with type 2 diabetes mellitus remains unclear. The aim of the present multicenter cross-sectional study was to investigate the relationship between drinking frequency, weekly alcohol consumption, daily alcohol consumption, and ED among Japanese patients with type 2 diabetes mellitus. Study subjects were 340 male Japanese patients with type 2 diabetes mellitus, aged 19-70 years, who had undergone blood tests at our institutions. A self-administered questionnaire was used to collect information on the variables under study. ED was defined as present when a subject had a Sexual Health Inventory for Men score8. Adjustment was made for age, body mass index, duration of type 2 diabetes mellitus, current smoking, hypertension, dyslipidemia, glycated hemoglobin, stroke, coronary artery disease, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. The prevalence of ED was 43.2% (147/340). The frequency of alcohol consumption and weekly alcohol consumption were independently inversely associated with ED (p for trend p = 0.001 and 0.004, respectively). The relationship between daily alcohol consumption and ED was an inverted J-shaped curve: alcohol consumption of less than 60 g, but not 60 g or more, per day was independently related to a lower prevalence of ED (p for quadratic trend = 0.003). In Japanese men with type 2 diabetes mellitus, an inverted J-shaped relationship between daily alcohol consumption and ED was observed, while frequency of alcohol consumption and weekly alcohol consumption were significantly inversely associated with ED.

Diabetes was significantly positively associated with urgency incontinence in several epidemiological studies. We examine the association between diabetic neuropathy, which we defined based on neuropathic symptoms, the absence of the Achilles reflex, and/or abnormal vibration perception, and urgency incontinence among Japanese patients with type 2 diabetes mellitus.Study subjects were 742 Japanese patients with type 2 diabetes mellitus, aged 19-70 years, who had undergone blood tests at our institutions. A self-administered questionnaire was used to collect information on the variables under study. Urgency incontinence was defined as present when a subject answered "once a week or more" to the question: "Within one week, how often do you leak urine because you cannot defer the sudden desire to urinate ?". Diabetic neuropathy was diagnosed if the patients showed two or more of the following three characteristics: neuropathic symptoms, the absence of the Achilles reflex, and/or abnormal vibration perception. Adjustment was made for sex, age, body mass index, duration of type 2 diabetes mellitus, current smoking, hypertension, dyslipidemia, glycated hemoglobin, stroke, coronary artery disease, insulin therapy, diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy.The prevalence of urgency incontinence was 8.6%. Diabetic neuropathy was independently positively associated with urgency incontinence: the adjusted OR was 2.20 (95%CI: 1.16-4.36). Associations between diabetic retinopathy or nephropathy and the prevalence of urgency incontinence were not significant.In Japanese patients with type 2 diabetes mellitus, only diabetic neuropathy was independently positively associated with urgency incontinence. Neurourol. Urodynam. 35:1024-1027, 2016. © 2015 Wiley Periodicals, Inc.

症例は52歳, 女性. 2001年5月に大腿骨骨頭置換術の術前検査で肝機能異常とHBs抗原陽性を指摘された. HBe抗原陰性, HBe抗体陽性, HBV-DNA検出感度以下であるにもかかわらず肝機能異常が持続した. 他の肝疾患の合併を考慮し精査を行ったところ抗核抗体160倍, 抗ミトコンドリア抗体陽性であり自己免疫性肝疾患の合併が疑われた. 腹腔鏡検査で溝状陥凹がみられた. 生検組織は慢性肝炎 (F3/A2) の像を呈しており, 門脈域には形質細胞の浸潤があったが胆管病変はなかった. 以上より肝障害の成因は自己免疫性肝炎と診断した. プレドニゾロンによるHBVの再活性化の予防を目的としてラミブジンを併用した. 治療開始後肝機能の改善があり, 開始2年後の現在まで経過は良好である. ラミブジンの併用でHBVの再活性化を来すことなくステロイド投与を実施できた症例を経験した.

Low incidence of reversal blood flow at the portal vein has been reported by measurement in larger and extrahepatic blood vessels but not in intrahepatic blood vessels in patients with liver cirrhosis. Moreover, there is little information regarding the incidence of reversal blood on the basis of the cause of liver cirrhosis. The aim of this study was to measure the reversal blood flow in the portal vein including intrahepatic branches in patients with alcoholic and viral cirrhosis.The blood flow in the portal vein and existence of portosystemic shunt were studied in 52 and 27 patients with alcoholic and viral cirrhosis, respectively, by Doppler ultrasonography. The parameters of liver function test and the prevalence of ascites and esophageal varices were compared between patients with and without reversal blood flow.Reversal blood flow at the portal vein was found only in patients with only alcoholic cirrhosis (17 of 52 patients) but not in any patients with viral cirrhosis (0 of 27 patients; p0.05). The incidence of portosystemic ascites and red color of esophageal varices was also higher in patients with alcoholic cirrhosis with reversal blood flow in the portal vein compared with patients without reversal blood flow (p0.05).Reversal blood flow in the portal vein is a characteristic feature of alcoholic cirrhosis. The presence of reversal blood flow indicates severe liver diseases, and this feature may have prognostic importance for patients with alcoholic cirrhosis.

A case of malignant thymoma presenting as an anterior neck mass is reported. The tumor extended from the thyroid gland to the superior mediastinum. It did not accumulate Tc-99m pertechnetate, but continued to accumulate Tl-201 at the late phase. A fine-needle aspiration cytology from the tumor showed tight clusters of epithelial cells with crowded ovoid nuclei. The tumor was initially diagnosed as thyroid carcinoma, clinically and cytologically. A thymoma with a dominant epithelial component has to be considered in the differential diagnosis of a suspected papillary carcinoma of the thyroid.

A 44-year-old Japanese woman with a history of living-related renal transplantation was treated with interferon-beta (IFN-beta) for chronic infection with sero-group 2 hepatitis C virus (HCV). Serum HCV-RNA titer was 160 kilo-international units/ml. Treatment with intravenous IFN-beta daily was given for 6 weeks. Serum HCV-RNA was undetectable at 3 weeks after initiating therapy. Renal graft rejection did not occur. Six months after completing therapy, she obtained sustained viral response. This case demonstrates that IFN-beta therapy safely induced clearance of HCV in a renal transplant recipient with stable renal function, low viral load and/or HCV sero-group 2.

A 42-year-old Japanese man was admitted to our hospital for investigation of abnormal liver function tests. He had no history of drug use, and drank little alcohol. Body mass index was 30. Serum was negative for viral markers and autoantibodies. Laparoscopy revealed diffuse small nodules on the liver surface. Liver biopsy revealed small nodules with pericellular fibrosis and macrovesicular fat deposition throughout the acini. Some inflammatory changes were observed. Liver cirrhosis due to non-alcoholic steatohepatitis (NASH) was diagnosed. NASH displays similar histological and laparoscopic characteristics to alcoholic liver diseases.

Subclinical hypothyroidism (SCH) has been associated with type 2 diabetes mellitus. However, it is unknown whether common complications of type 2 diabetes, such as diabetic nephropathy, are also present with SCH. Here, we investigated the association between SCH and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. In this multicenter cross-sectional study, we recruited 414 such patients who had no previous history of thyroid disease. Serum thyroid hormone levels and the urinary albumin:creatinine ratio were measured. SCH was defined as an elevated thyroid-stimulating hormone (TSH) level (>4.0 mIU/L), and diabetic nephropathy was defined as urinary albumin/creatinine ratio ≥300 mg/g. The prevalence of SCH was 8.7% (n = 36) among patients with type 2 diabetes mellitus. The SCH group had a higher prevalence of dyslipidemia (p = 0.008) and diabetic nephropathy (p = 0.014) than the euthyroid group. Multivariate analysis identified significant positive associations between diabetic nephropathy and SCH (odds ratio [OR], 3.51; 95% confidence interval [CI], 1.10-10.0; p = 0.034), hypertension (OR, 4.56; 95% CI, 1.69-14.7; p = 0.001), and smoking (OR, 3.02; 95% CI, 1.14-7.91; p = 0.026). SCH may be independently associated with diabetic nephropathy in Japanese patients with type 2 diabetes mellitus.

Background/Aims: Gene transfer using recombinant Moloney murine leukemia viruses (rMoMuLV) requires mitosis of the target cell. Previously, we and others have used partial hepatectomy for induction of hepatocellular proliferation for gene transfer to the liver in vivo by exsanguineous perfusion with rMoMuLV. We hypothesized that induction of hepatocellular proliferationby combined administration of two hepatocellular mitogens, hepatocyte growth factor (HGF) and triiodothyronine (T3), should permit rMoMuLV-mediated gene transfer into liver without invasive approaches. Methods: HGF (1 mg/kg) was perfused continuously into the portal vein of Wistar male rats and T3 (2 mg/kg) was injected subcutaneously. Twenty-four hours after injecting HGF and T3, the state of proliferation of hepatocytes was estimated from the incorporation of 5′-bromo-2′-deoxy-uridine (BrdU). The amphotropic retroviral receptor (Ram-1) expression of liver was evaluated at different time points after injecting HGF and T3 by means of Northern blotting using Ram-1 cDNA probe. In order to evaluate the role of hormone treatment on gene transfer, the liver was perfused exsanguineously with rMoMuLV 24 h after injection with hormones. Results: Rats treated with a combination of HGF and T3 expressed BrdU and β-galactosidase in 8.3% and 0.7% of hepatocytes, respectively. On the other hand, there was near absence of gene transfer in untreated rats perfused with rMoMuLV. Twenty-four hours after the initial manipulation, abundant expression of Ram-1 mRNA was observed in rat hepatocytes treated with HGF plus T3. Conclusions: Stimulation of hepatocellular mitosis and upregulation of Ram-1 expression by HGF and T3 augment retrovirus-mediated gene transfer into hepatocytes.

ObjectiveWe estimated the prevalence of nocturnal intermittent hypoxia, a surrogate marker of obstructive sleep apnoea, among type 2 diabetes mellitus (T2DM) patients and examined the association between nocturnal intermittent hypoxia and microvascular diseases.Design and methodsWe recruited 513 Japanese patients (292 men and 221 women) with T2DM. Nocturnal intermittent hypoxia was diagnosed using the 3% oxygen desaturation index, with less than five events per hour corresponding to normal and five events or more per hour corresponding to nocturnal intermittent hypoxia.ResultsThe prevalence of nocturnal intermittent hypoxia was 45.4% among T2DM patients. The nocturnal intermittent hypoxia group was older and had a higher BMI, greater weight change since the age of 20 years, higher smoking rate and increased prevalence of hypertension, hyperlipidaemia, microalbuminuria and macroalbuminuria. Microalbuminuria (model 1: odds ratio (OR), 3.41; 95% CI, 1.85–6.40; model 2: OR, 3.69; 95% CI, 1.85–7.59 and model 3: OR, 3.12; 95% CI, 1.45–6.95) and nephropathy (model 1: OR, 4.51; 95% CI, 1.58–15.1; model 2: OR, 7.31; 95% CI, 2.11–31.6 and model 3: OR, 5.23; 95% CI, 1.45–23.8) were derived as factors from all the three statistical models and constantly associated with nocturnal intermittent hypoxia only in women.ConclusionsNocturnal intermittent hypoxia was highly prevalent among T2DM patients and may be an independent associated risk factor for microalbuminuria in Japanese women with T2DM.

We investigated the alteration of nutritional status in 144 patients who were treated for the first time with endoscopic sclerotherapy or endoscopic variceal ligation during their therapies. The serum levels of albumin, cholinesterase and total cholesterol were compared before and after treatment. The serum level of cholinesterase declined significantly. To investigate the impact of aging on the changes of nutritional status we divided all patients into two groups: (1) under 65 years, and (2) over 65 years. The decline of serum albumin of elderly patients (n=65) was significantly greater than that of younger patients (n=79). A branched-chain amino acid (BCAA)-enriched nutrient mixture for nutritional treatment significantly suppressed the decline of serum albumin in elderly patients. Nutritional treatment with a BCAA-enriched nutrient mixture should be considered during endoscopic therapy for esophageal varices, especially in elderly patients.

We treated a 66-year-old woman with hepatic encephalopathy secondarily induced by an intrahepatic portosystemic venous shunt (IPSVS). In serial observations, the volume of the liver became smaller and encephalopathy could not be controlled with conservative therapy. We occluded the IPSVS successfully using percutaneous transcatheter embolization with micro coils. Following embolization, encephalopathy disappeared and blood flow of all branches of portal vein improved. In cases with an IPSVS without liver cirrhosis, blood flow in the portal vein and liver volume must be followed carefully, and interventional radiology may be considered effective in those who do not show a satisfactory response to conservative therapy.

A 54-year-old Japanese woman with primary biliary cirrhosis (PBC) was admitted to our hospital due to hepatic coma and refractory pleural effusion. The physical examination revealed clubbed fingers and collateral veins. The patient had an increased alveolar-arterial oxygen gas tension difference. The levels of anti-mitochondrial antibody (AMA) and AMA M2 was 80 times normal. A technetium 99m-labeled macro-aggregated human albumin scintigram showed uptake in the spleen and the kidneys. A diagnosis of hepatopulmonary syndrome (HPS) was made. HPS may be overlooked because of the lack of symptoms. We conclude that closer attention should be paid to the occurrence of HPS.

We previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this study was to explore the effects of these agents on hepatic insulin sensitivity directly using a perfused GK rat liver model.GK rats were treated with oral pioglitazone (6 or 10 mg/kg body weight), EPA (1 or 2 g/kg body weight), or fenofibrate (30 mg/kg body weight) for 2 weeks. Livers were perfused in situ with glucagon or with glucagon and insulin, and hepatic glucose outputs were measured.In the pioglitazone-treated GK rats, blood glucose levels were significantly decreased. In the pioglitazone- and EPA-treated GK rats, insulin infusion significantly attenuated hepatic glucose output stimulated by glucagon. In the fenofibrate-treated GK rats, fat deposits in the hepatocytes were decreased, and glucose output elicited by glucagon was significantly decreased compared with that in the untreated GK rats, whereas insulin infusion did not affect glucose output by glucagon.These findings suggest that pioglitazone and EPA may improve glucose tolerance by directly increasing hepatic insulin sensitivity, while fenofibrate may improve glucose tolerance by improving hepatic glycogen metabolism in the GK rats. We previously reported that the Goto-Kakizaki (GK) rat, an animal model of type 2 diabetes, has hepatic insulin resistance using a perfused rat liver model. Pioglitazone, eicosapentaenoic acid (EPA), and fenofibrate are antihyperlipidemic agents and improve glucose tolerance. There have been few studies showing that these agents directly improve hepatic insulin sensitivity in type 2 diabetes mellitus. The aim of this study was to explore the effects of these agents on hepatic insulin sensitivity directly using a perfused GK rat liver model.

A 25-year-old woman with no history of liver disease developed liver dysfunction associated with severe jaundice and general malaise following a prolonged therapy with minocycline for acne vulgaris. Serum anti-nuclear antibody was detected and immunoglobulin G level was elevated. Symptoms resolved and liver function normalized following minocycline discontinuation and corticosteroid administration. Our diagnosis was drug-induced hepatitis with autoimmune features, as liver histology revealed acute hepatitis. Drug-induced hepatitis should be considered when liver dysfunction or systemic symptoms develops during long-term minocycline therapy.

• L0625 DEVELOPMENT OF AN EFFICIENT NONVIRAL GENE TRANSFER METHOD TO HEPATOCYTES USING CATIONIC LIPOSOME AND URSODEOXYCHOLIC ACID. K Tada, H Minami, Y Oka, H Iuchi, SMF Akbar, N Horiike, N Roy Chowdhury*, J Roy Chowdhury*, M Onji. The Third Dept of Internal Medicine, Ehime University School of Medicine, Japan, and the Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY.