Hyperglycemia-induced embryonic malformations may be due to an increase in radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. In the past, we have investigated the role of the glutathione-dependent antioxidant system and GSH on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational day 11 showed a significantly higher frequency of embryonic malformations (neural lesions 21.5 vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth retardation than those of normal mothers. The formation of intracellular reactive oxygen species (ROS), estimated by flow cytometry, was increased in isolated embryonic cells of diabetic rats on gestational day 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly lower than that of normal rats. The activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of diabetic rats was significantly low, associated with reduced expression of gamma-GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to diabetic rats during the period of maximal teratogenic susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3 vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of ROS, leading to normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs. 47.4%), and growth retardation with the restoration of GSH contents. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes.

BackgroundHepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC.Methods and FindingsHere we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99±1.8 µg/ml in men and 6.06±2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s–40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis.ConclusionAIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

Independent of classical cardiovascular risk factors, height was found to be inversely associated with high WBC count, especially for those with a BMI ≥ 23 kg/m. Compared to high stature, short stature appears to convey an inflammatory disadvantage among Japanese men, especially those with a BMI ≥ 23 kg/m.

Two cases of Behcet's disease associated with myelodysplastic syndrome are described. Both patients showed a chromosomal abnormality, trisomy 8. Based on the laboratory findings in our patients and a careful review of the literature of similar cases, the association of the chromosomal abnormality with the pathogenesis of Behcet's disease is suggested.

BackgroundOur previous study showed that height is inversely associated with the risk of stroke in middle-aged Japanese men, particularly in those with a low body mass index (BMI). Since height is regarded as a surrogate maker of childhood social and physical condition, while BMI may reflect primarily on the current physical condition, a detailed analysis of those with a lower BMI may elucidate the effects of childhood conditions. On the other hand, dyslipidemia is recognized as a prominent risk factor for cardiovascular disease. However, no studies have reported on the association between height and dyslipidemia accounting for BMI status.MethodsWe conducted a hospital-based general population cross-sectional study of 3016 Japanese men aged 30–59 years. Dyslipidemia is defined by the Japan Atherosclerosis Society (JAS) Guidelines as follows: triglycerides (TG) ≥ 150 mg/dL and/or low-density lipoprotein-cholesterol (LDL) ≥ 140 mg/dL, and/or high-density lipoprotein-cholesterol (HDL) < 40 mg/dL, and/or lipid lowering medication use.ResultsIndependent of classical cardiovascular risk factors, height was found to be inversely associated with dyslipidemia in subjects with a BMI <25 kg/m2 but not in subjects with a BMI ≥25 kg/m2. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of dyslipidemia for an increment of one standard deviation (SD) in height (5.7 cm) were 0.90 (0.82–0.99) for subjects with a BMI < 25 kg/m2 and 1.02 (0.89–1.17) for subjects with a BMI ≥ 25 kg/m2.ConclusionHeight is inversely associated with dyslipidemia in those with a BMI < 25 kg/m2 but not with a BMI ≥ 25 kg/m2.

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non-obese women with a history of GDM and eight non-obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18+/-0.34 vs 2.26+/-0.29 x 10(-2) min(-1), p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56% of that observed in control subjects (1250+/-87.4 vs 2223+/-304.3 pmol l(-1) min, p < 0.01). Our results indicate that in former GDM patients, who are japanese and non-obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved.

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Objectives Several studies have reported the association between sleep apnea syndrome and insulin resistance. Being overweight is known risk factor both for sleep apnea syndrome and insulin resistance. However, no studies have reported on the association between serum triglyceride levels in relation to high-density lipoprotein cholesterol (TG-HDL) ratios (a marker of insulin resistance) and sleep apnea syndrome accounting for body mass index (BMI) status. Methods Subjects for the present cross-sectional study consisted of 1,528 men aged 30-69 years undergoing pulse oximetry at a sleep disorders clinic for sleep apnea syndrome. Sleep apnea syndrome was diagnosed as a 3 % oxygen desaturation index (ODI) of C15 events/h. Results Among study participants, 241 men were diagnosed with sleep apnea syndrome. Independent of classical cardiovascular risk factors, TG-HDL was significantly positively associated with sleep apnea syndrome in participants with a BMI \25 kg/m 2 , but not in participants with a BMI C25 kg/m 2 . The multivariable adjusted odds ratio (OR) and 95 % confidence interval (95 % CI) of sleep apnea syndrome per Log TG-HDL was 2.03 (95 % CI: 1.36-3.03) for a BMI \25 kg/m 2 and 1.23 (95 % CI: 0.89-1.70) for a BMI C25 kg/m 2 . Conclusions An independent positive association between TG-HDL levels and risk of sleep apnea syndrome was observed in participants with a BMI of \25 kg/m 2 , but not in participants with a BMI C25 kg/m 2 . TG-HDL levels could be an efficient tool to estimate the risk of sleep apnea syndrome in non-overweight Japanese men.