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Adiponectin is an adipocyte-specific secretory protein, which possesses antidiabetic and antiatherosclerotic properties. Adiponectin exists as multimers in serum, and high-molecular-weight (HMW) adiponectin is particularly considered to be the active form of the protein. The objective of the present study was to examine whether decreased HMW adiponectin is a predictor of progression to metabolic syndrome during a 6-year follow-up period in Japanese men. The study subjects were 416 Japanese men without metabolic syndrome, aged 30 to 59 years at baseline, who had participated in annual health checkups in both 2000 and 2006. Low concentration of HMW adiponectin (< or =2.65 microg/mL) was associated with substantially higher hazard ratio of the progression to metabolic syndrome after adjustment for age and body mass index (hazard ratio, 1.561; 95% confidence interval, 1.051-2.292; P = .028). The number of subjects with the progression to metabolic syndrome in each tertile based on baseline HMW adiponectin concentration was significantly different among the 3 groups (HMW adiponectin: chi(2) = 7.473, P = .0238; total adiponectin: chi(2) = 4.477, P = .1066; HMW-total adiponectin ratio: chi(2) = 1.676, P = .4325). It was suggested that decreased HMW adiponectin is a predictor of the progression to metabolic syndrome in a 6-year follow-up study of Japanese men. Furthermore, it was suggested longitudinally that measuring HMW adiponectin is efficient to predict the progression to metabolic syndrome compared with measuring total adiponectin or HMW-total adiponectin ratio.

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single-nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently, observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1250 cases (562 adenocarcinoma, 391 squamous cell carcinoma and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5-3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without; however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.

Adipokines play crucial roles in obesity-related insulin resistance in adults, but little is known in the general adolescent population. This study was designed to investigate the relationships between adipokines and metabolic parameters, the insulin resistance index, and proinflammatory cytokines in the general population of Japanese male adolescents. We studied 662 Japanese male high school students aged 16 to 17 years and 282 healthy Japanese male adults aged 30 to 61 years who received annual health checkups. High-molecular weight (HMW) adiponectin levels were significantly lower in adolescents (4.18 +/- 2.24 microg/mL) than in adults (4.84 +/- 3.20 microg/mL), despite body mass index (BMI) being significantly lower in adolescents. The HMW adiponectin levels correlated negatively with BMI and the homeostasis model assessment of insulin resistance index (HOMA-IR) in adults. In adolescents, HMW adiponectin correlated negatively with BMI and waist circumference, but not with HOMA-IR or other metabolic parameters except high-density lipoprotein cholesterol. Leptin levels correlated positively with HOMA-IR, triglycerides, tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 and negatively with high-density lipoprotein cholesterol even after adjustment for BMI. These findings suggest that serum leptin is a more useful biomarker of fat accumulation-related insulin resistance, inflammation, and metabolic abnormalities than HMW adiponectin in the general population of male adolescents. The inverse correlation between adiponectin and insulin resistance may manifest in the later phase of obesity development.

Bone and soft tissue sarcomas (BSTSs) are rare malignant tumors of mesenchymal origin. Although BSTSs frequently occur in some hereditary cancer syndromes with germline mutations of DNA repair genes, genetic factors responsible for sporadic cases have not been determined. In the present study we undertook a case-control study and analyzed possible associations between the susceptibility to BSTS and the single nucleotide polymorphisms (SNPs) in DNA repair genes. Genomic DNAs extracted from case and control peripheral blood leukocytes were genotyped by pyrosequencing. For candidate polymorphisms, we chose 50 non-synonymous missense SNPs, which we have previously been identified by resequencing 36 DNA repair genes among the Japanese population. In the first screening, we analyzed 240 cases and 685 controls and selected six SNPs at the significance level of P < 0.1 (Fisher's exact test). The six SNPs were further analyzed in the second genotyping on an additional set of 304 cases and 834 controls. In the joint analysis (the first and second genotyping combined) of 544 cases and 1378 controls, Cys1367Arg of the WRN gene was found to be a protective factor of BSTS (odds ratio = 0.66, 95% confidence interval = 0.49-0.88, P = 0.005). An exploratory subgroup analysis without multiple comparison adjustment suggested that the WRN-Cys1367Arg SNP is associated with soft tissue sarcomas, sarcomas with reciprocal chromosomal translocations and malignant fibrous histiocytoma.

Adiponectin is an adipocyte-specific secretory protein that possesses antidiabetic and antiatherosclerotic properties. Recent studies have demonstrated that the high molecular weight (HMW) multimer form is the active form of this protein. In patients with type 2 diabetes mellitus, HMW-total adiponectin ratio was reported to be a more useful marker than total adiponectin in the prediction of insulin resistance and metabolic syndrome. In the present study of healthy Japanese male subjects without any medication, we investigated the hypothesis that measuring only HMW adiponectin may be as effective as HMW-total ratio to predict insulin resistance and/or metabolic syndrome. This was a working community-based cross-sectional study of 637 male subjects aged 30 to 65 years. Total and HMW adiponectin concentrations in serum were measured by enzyme-linked immunosorbent assay using commercially available kits. Serum HMW adiponectin level was inversely correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = -0.375, P < .0001) even after adjustment for age and body mass index (r' = -0.245, P < .0001). When we divided the study subjects into quartile groups with equal numbers of subjects, HOMA-IR in the 4 groups based on serum HMW adiponectin level was significantly different (P < .01). Metabolic syndrome score in the 4 groups based on serum HMW adiponectin level was also significantly different (P < .01). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.73) to evaluate the presence of insulin resistance (HOMA-IR >2.5) was larger than that of total adiponectin (0.68) or HMW-total ratio (0.70). Area under the curve of receiver operator characteristic curves of HMW adiponectin (0.70) to evaluate the presence of metabolic syndrome (body mass index-based modified criteria) was also larger than that of total adiponectin (0.65), but equal to that of HMW-total ratio (0.70). These results suggest that simply measuring HMW adiponectin may be as effective as HMW-total ratio to evaluate the presence of insulin resistance and metabolic syndrome, at least in nondiabetic subjects who are not receiving any medication.

Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05

Case Report: The patient was a 50-year old male who was found to have a high cholesterol level during a routine health check up at work 5 years before and was examined at Keio University Hospital. Lipoprotein electrophoresis on agarose gel revealed type III hyperlipidemia, and a screening test yielded the following values (mg/dl): total cholesterol, 420; TG, 138; and HDL-cholesterol, 105. Turbidimetric immunoassay showed that the apolipoprotein E (apoE) level was below the limit of detection. Since he was 25 years old, the patient had sometimes noticed xanthomas on his knees and eyelids, and for that reason we made a diagnosis of apoE deficiency associated with type III hyperlipidemia. We tried using SDS-polyacrylamide gel electrophoresis, Western blot, and the protein chip method to detect apoE in this case, but the level was below the limit of detection by the first two methods, and it was so low that it was detected near the sensitivity limit of the protein chip method. Diet therapy, statin therapy, and fibrate therapy have been continued, and the latest data are: total cholesterol, 373; TG, 95; and HDL-cholesterol, 83. No manifestations associated with arteriosclerotic disease other than mild xanthomas have been observed.

Single nucleotide polymorphisms (SNPs) were searched for in 36 genes involved in diverse DNA repair pathways, and 50 nonsynonymous (associated with amino acid changes) SNPs identified were assessed for associations with lung cancer risk by a case-control study consisting of 752 adenocarcinoma cases, 250 squamous cell carcinoma cases and 685 controls. An SNP, Arg72Pro, of the TP53 gene encoding a DNA damage response protein showed the strongest association with squamous cell carcinoma risk (OR Pro/Pro vs. Arg/Arg = 2.2), while 2 other SNPs, Phe257Ser of the REV gene encoding a translesion DNA polymerase and Ile658Val of the LIG4 gene encoding a DNA double-strand break repair protein, also showed associations (OR Ser/Ser vs. Phe/Phe = 2.0 and OR Ile/Val vs. Ile/Ile = 0.4, respectively). An SNP, Thr706Ala, in the POLI gene encoding another translesion DNA polymerase was associated with adenocarcinoma and squamous cell carcinoma risk, particularly in individuals of ages < 61 years (OR Ala/Ala + Ala/Thr vs. Thr/Thr = 1.5 and 2.4, respectively). POLI is the human counterpart of PolI, a strong candidate for the Par2 (pulmonary adenoma resistance 2) gene responsible for adenoma/adenocarcinoma susceptibility in mice. The present results suggest that these 4 SNPs function as genetic factors underlying lung cancer susceptibility by modulating activities to maintain the genome integrity of each individual., (2004 Wiley-Liss, Inc.)

The metabolic syndrome is characterized by a blunted insulin-mediated glucose uptake in various cell types. We compared the glucose uptake characteristics of Epstein-Barr virus (EBV)-transformed lymphoblasts obtained from young men with vs without metabolic and cardiovascular evidence of metabolic syndrome. From a population of 218 men, 20- to 25-year-old, 10 men with a systolic blood pressure (BP) > or =130 mm Hg and family history of hypertension were assigned to a high BP (HBP) group, and 10 with a BP < or =110 mm Hg, and no family history of hypertension was assigned to a low BP (LBP) group. Multiple clinical and metabolic characteristics were examined in both groups and compared. Peripheral lymphocytes from HBP and LBP subjects were EBV-transformed, and the glucose transporter (Glut)-mediated glucose uptake from each group was compared in lymphoblasts. Body mass index, fasting glucose, immunoreactive insulin, insulin resistance index based on a homeostasis model assessment (HOMA-R), and total and low-density lipoprotein cholesterol were significantly higher in the HBP than the LBP subgroup (whole-body insulin resistance). Baseline Glut-mediated and Glut-mediated insulin-stimulated glucose uptake by lymphoblasts from the HBP group were significantly lower than by lymphoblasts from the LBP group (cellular insulin resistance). The net increment in Glut-mediated glucose uptake by insulin was inversely correlated with HOMA-R. In conclusion, cellular insulin resistance in EBV-transformed lymphoblasts is associated with young Japanese subjects with HBP. The net increment in Glut-mediated glucose uptake by insulin in lymphoblasts may be a useful intermediate phenotype to study genetic aspects of the metabolic syndrome.

GPR40 is a member of the G-protein-coupled receptors. Recent studies suggest that GPR40 is highly expressed in pancreatic beta cells and insulin-secreting cell lines, and that fatty acids increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion by activating GPR40. Despite identification of the Arg211His polymorphism in the GPR40 gene, there have been no clinical studies concerning this polymorphism. The present study was performed to investigate the effects of the GPR40 gene Arg211His polymorphism on clinical and metabolic parameters, including serum insulin level, in 327 healthy Japanese men, using the TaqMan polymerase chain reaction method. Serum insulin level, homeostasis model of insulin resistance (HOMA-IR), and beta-cell function (HOMA-beta were significantly different (P = .0075, .0152, and .0039, respectively) and were lowest in Arg/Arg homozygotes and highest in His/His homozygotes, although plasma glucose and serum lipids were not significantly different. Multiple regression analyses showed that serum insulin level, HOMA-IR, and HOMA- beta were significantly correlated with this polymorphism after adjusting for age and body mass index. After Bonferroni's correction for multiple comparisons was made, only HOMA- beta was significantly different among the 3 genotypes. These results suggest that the Arg211His polymorphism in the GPR40 gene may contribute to the variation of insulin secretory capacity in Japanese men.

Purpose: To report anatomic and visual outcomes of vitrectomy and indocyanine green (ICG)-assisted peeling of the retinal internal limiting membrane (ILM) in the treatment of diffuse diabetic macular edema., Methods: In a retrospective interventional case series, 15 eyes of 11 patients with refractory diffuse diabetic macular edema underwent pars plana vitrectomy with removal of the ILM, which was stained by intravitreal injection of ICG (0.1-0.2 ml of 0.5% ICG), performed by a single surgeon. The patients were followed up for 14-28 months (mean 20.5 months). The main outcome measures were assessment of macular edema by optical coherence tomography and determination of visual acuity and visual field., Results: Intravitreal ICG visualized the ILM to facilitate complete removal of the structure. Qualitative assessment of optical coherence tomography images at the end of follow-up revealed that retinal thickness in the macula appeared nearly normal with or without reappearance of foveal pit in 11 of the 15 eyes (73.3%), decreased in 3 eyes (20.0%), and did not change in 1 eye (6.6%). Best-corrected visual acuity at the end of follow-up improved by 2 lines or more in 4 eyes (26.7%), virtually unchanged in 6 eyes (40.0%), and deteriorated by 2 lines or more in 5 eyes (26.7%). The mean logMAR visual acuity was 0.680 (approximately 12/60) preoperatively and 0.812 (approximately 9/60) postoperatively, the difference being not statistically significant (paired t-test, P=0.445). Seven (46.7%) of the 15 eyes developed optic nerve atrophy that occurred gradually within 6 months after surgery and caused irreversible peripheral visual field defect predominantly affecting the nasal field., Conclusion: Intravitreal application of ICG is beneficial in uneventful ILM peeling to help resolution of diffuse diabetic macular edema, but it may potentially damage the optic nerve fibers and lead to unfavorable visual outcomes.

Background/aims: Since a novel polypeptide named adiponectin was shown to prevent the development of steatosis and steatohepatitis in animal models, we studied whether it was also possible in a clinical situation., Methods: Associations between serum adiponectin levels and serum transaminase activities were studied in 791 Japanese males who were not heavy drinkers, and had no autoimmune or HBV- or HCV-induced liver diseases., Results: Various markers of metabolic diseases including levels of body mass index (BMI), serum triglyceride, total cholesterol, and insulin resistance assessed by the homeostasis model were significantly higher in subjects with increased transaminase activities when compared to those with normal activities. Single regression analyses demonstrated that the logarithmic serum adiponectin level was inversely correlated with the levels of logarithmic serum AST (r=-0.229, P<0.0001), ALT (r=-0.305, P<0.0001), and gammaGTP (r=-0.278, P<0.0001). Even in multiple regression analyses in which subjects' age and levels of BMI, serum triglyceride, total cholesterol, and insulin resistance were adjusted, the inverse correlations were significant (P=0.0426, 0.0332, and 0.0011, respectively)., Conclusions: Hypoadiponectinemia may worsen liver diseases associated with metabolic diseases in clinical cases. In addition to aggravation of insulin resistance and hyperlipidemia, some hypoadiponectinemia specific mechanisms may stand behind the association.

It has been reported that the serum adiponectin level was negatively correlated with body mass index (BMI), insulin resistance index, and triglycerides and was positively correlated with high-density lipoprotein cholesterol in several cross-sectional studies. However, the causal relationship has not been elucidated. We investigated whether the baseline adiponectin level could predict subsequent changes in insulin resistance, lipid profile, or body weight in a 2-yr longitudinal study. This study included 590 male Japanese subjects, aged 30-65 yr, who received annual health checkups in both 2000 and 2002. Blood pressure, heart rate, and anthropometric and metabolic parameters, including serum insulin and adiponectin levels, were determined. The insulin resistance index was calculated based on homeostasis model assessment. Baseline adiponectin level was not correlated with the subsequent change in lipid profile or BMI in 2 yr after adjustment for each baseline value. However, the baseline adiponectin level was negatively correlated with subsequent changes in insulin and insulin resistance index based on homeostasis model assessment, even after adjustment for change in BMI (r = -0.162 and r = -0.140, respectively). These findings suggest that the serum adiponectin concentration predicts subsequent changes in insulin resistance, but not in lipid profile or body weight.

Type 1 diabetes is characterized by cell-mediated autoimmune destruction of pancreatic beta cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. Recently, it was reported that a polymorphism of the stromal cell-derived factor-1 (SDF-1) (a kind of chemokine) gene was associated with early onset of type 1 diabetes in Caucasians. Therefore, we examined SDF-1 gene polymorphism in Japanese type 1 diabetes in this study. We examined the SDF-1 gene polymorphism (801G-->A) in 298 unrelated Japanese type 1 diabetic patients and 270 healthy subjects by the TaqMan PCR method. Allelic and genotypic frequencies of the SDF-1 A variants were similar in overall type 1 diabetic patients and healthy subjects. We then stratified the patients by their onset pattern (acute vs. slow onset) and islet-associated autoantibody positivity. However, no significant difference was found among each group of type 1 diabetes. Furthermore, unlike the previous report in "Caucasian" type 1 diabetics, the SDF-1 A variant was not associated with early onset of the disease in Japanese type 1 diabetics. The SDF-1 gene polymorphism was not associated with onset age (or onset pattern) of type 1 diabetes in Japanese. Further study is necessary to conclude whether SDF-1 gene polymorphism affects the onset age in type 1 diabetes in general.

Purpose: There are cases when ocular pain persists long after ocular surgery and can not be reduced by anti-inflammatory drugs. Our purpose was to evaluate the effect of stellate ganglion block(SGB) on such prolonged post-operative ocular pain., Method: The subjects were 35 patients. Divided into two groups. One we called the nociceptive pain group, containing 29 cases in which the trigeminal nerve in the orbit or passing through it was intact. The other we called the neuropathic pain group, containing 6 cases in which pain accompanied paralysis of the trigeminal nerve. SGB was performed two times per week. SGB was deemed effective when pain was reduced markedly and the administration of anti-inflammatory drugs became almost unnecessary., Results: SGB was 96.6% effective in the nociceptive pain cases with the SGB performed an average of 5.9 times. On the other hand, in the neuropathic pain group, even though SGB was performed an average of 52.6 times it was only 66.7% effective., Conclusions: SGB may be useful for the treatment of prolonged post-operative ocular pain, but the elimination of neuropathic pain is more difficult than the elimination of nociceptive pain.

Background: Our previous studies suggested that serum gamma-glutamyl transpeptidase (GGTP) level was correlated with insulin resistance level estimated by the homeostasis model assessment in teetotalers and occasional drinkers. In the surveys, strong correlation between GGTP and triglyceride also was observed. This study examined whether the correlation held true for regular drinkers., Methods: Seven hundred and seventeen male subjects in annual health checkups were divided into three groups according to their drinking styles and further divided into four subgroups according to their serum GGTP levels. In the other surveys, they were ranked by their amount of ethanol consumption. The correlation between GGTP and insulin resistance level was studied in each group., Results: Single regression analysis and analysis of variance showed that GGTP level was significantly correlated with insulin resistance level as determined by the homeostasis model assessment, as well as with triglyceride level regardless of subjects' drinking styles. The associations were confirmed by multiple regression analyses in which age, levels of uric acid, total cholesterol, high-density lipoprotein cholesterol, and body mass index were adjusted, at least in nondrinkers or light drinkers. However, the multiple regression analyses indicated that the association between GGTP and insulin resistance level was not significant in subjects who take ethanol more than five times per week. The studies according to the amount of subjects' ethanol consumption indicated that the association between GGTP and insulin resistance was significant in the subjects who take ethanol up to 280 g/week., Conclusion: Individual variation in insulin resistance status may contribute to individual variations of sensitivity of GGTP to ethanol intake, at least in light drinkers.

Hypertension is often accompanied with type-2 diabetes mellitus. Based on insulin resistance and/or resultant hyperinsulinemia, diabetes mellitus, hypertension, lipid disorders and atherosclerotic vascular diseases are often seen in the same individuals. Lifestyle modification to reduce insulin resistance is very important to manage diabetic patients with hypertension. When the doctors use anti-hypertensive medication, we have to take care not to worsen glucose or lipid profiles. Taking recent guidelines from US, Japan and Europe into considerations, blood pressure of diabetic patients should be controlled below 130-135/80 mmHg. ACE inhibitors, angiotensin II receptor antagonists are commonly recommended as first-line medicine to choose. However, Ca-channel blockers, alpha 1-blockers, beta-blockers and diuretics are often needed to achieve the goal: preventing organ damage which would be the most important issue for diabetic patients.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.

Adiponectin is an adipocyte-derived protein, which possesses an anti-atherosclerotic action and improves insulin sensitivity. Peroxisome proliferator-activated receptor gamma (PPAR(gamma)) regulates the transcription of many adipocyte-specific genes. A Pro12Ala polymorphism has been detected in the PPAR(gamma)2 gene, and this substitution has been reported to reduce transactivation activity in vitro. We hypothesized that individuals possessing this Ala12 allele may have a lower serum adiponectin level, because of the observation that PPAR(gamma) agonists increase the plasma adiponectin level in humans. To test this hypothesis, we investigated the effects of the PPAR(gamma)2 Pro12Ala polymorphism on anthropometric and metabolic parameters, including serum adiponectin level, in 478 Japanese men and 117 women aged 30 to 65 years. There were no homozygous subjects for the Ala12 allele of the PPAR(gamma)2 gene in this study. Plasma adiponectin levels were significantly lower in subjects with the Ala12 allele in the Japanese population of both sexes, although body mass index (BMI), plasma glucose, serum lipids, and insulin resistance index were not significantly different between subjects with and without this polymorphism. It is suggested that the Pro12Ala polymorphism of the PPAR(gamma)2 gene may reduce serum adiponectin level in the Japanese population., (Copyright 2002, Elsevier Science (USA). All rights reserved.)