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1.  Combinational risk factors of metabolic syndrome identified by fuzzy neural network analysis of health-check data 
Lifestyle-related diseases represented by metabolic syndrome develop as results of complex interaction. By using health check-up data from two large studies collected during a long-term follow-up, we searched for risk factors associated with the development of metabolic syndrome.
In our original study, we selected 77 case subjects who developed metabolic syndrome during the follow-up and 152 healthy control subjects who were free of lifestyle-related risk components from among 1803 Japanese male employees. In a replication study, we selected 2196 case subjects and 2196 healthy control subjects from among 31343 other Japanese male employees. By means of a bioinformatics approach using a fuzzy neural network (FNN), we searched any significant combinations that are associated with MetS. To ensure that the risk combination selected by FNN analysis was statistically reliable, we performed logistic regression analysis including adjustment.
We selected a combination of an elevated level of γ-glutamyltranspeptidase (γ-GTP) and an elevated white blood cell (WBC) count as the most significant combination of risk factors for the development of metabolic syndrome. The FNN also identified the same tendency in a replication study. The clinical characteristics of γ-GTP level and WBC count were statistically significant even after adjustment, confirming that the results obtained from the fuzzy neural network are reasonable. Correlation ratio showed that an elevated level of γ-GTP is associated with habitual drinking of alcohol and a high WBC count is associated with habitual smoking.
This result obtained by fuzzy neural network analysis of health check-up data from large long-term studies can be useful in providing a personalized novel diagnostic and therapeutic method involving the γ-GTP level and the WBC count.
PMCID: PMC3469424  PMID: 22853735
Data mining; Combinational risk factor; Fuzzy neural network; Glutamyltranspeptidase; Lifestyle disease; Personalized diagnostic method; White blood cell
2.  A new manual method for assessing elbow valgus laxity 
A screening of ulnar collateral ligament insufficiency is required for overhead throwers, since secondary pathologic changes result from an increased elbow valgus laxity. We developed a new manual method for assessing elbow valgus laxity and investigated the reliability of this method and its correlation with ultrasonographic assessment.
We defined elbow valgus laxity as the difference between the shoulder external rotation angle (ER angle) measured with the elbow in 90 degrees flexion and that measured with the elbow in extension because ER angle measured with the elbow in 90 degrees flexion includes elbow valgus laxity and ER angle with the elbow in extension does not include it. ER angle measurement with the elbow in extension involved the use of a custom arm holder. Three examiners each measured elbow valgus laxity by the new method in 5 healthy volunteers. Intraobserver and interobserver reliability was evaluated by calculating the intraclass correlation coefficient. We then assessed 19 high-school baseball players with no complaints of shoulder or elbow pain. Elbow ultrasonography was performed with a 10-MHz linear transducer with the elbow in 90 degrees flexion, and the forearm in the neutral position, and the width of the medial joint space at the level of the anterior bundle was measured. Elbow valgus laxity assessed by ultrasonography was defined as the difference between the medial joint space width with gravity stress and that without gravity stress. Increased elbow valgus laxity assessed by both our method and ultrasonography was defined as the difference between the laxity of the elbow on the throwing side and that on the contralateral side. Pearson's correlation coefficient (r) was calculated to evaluate the relationship between increased elbow valgus laxity obtained by our manual method and that by ultrasonography.
Intraobserver reliability ranged from 0.92 to 0.98, and interobserver reliability was 0.70. The increased elbow valgus laxity assessed by our method was significantly correlated with that assessed by ultrasonographic assessment (P = 0.019, r = 0.53).
Elbow valgus laxity can be assessed by our method. This method may be useful for screening for insufficiency of the ulnar collateral ligament.
PMCID: PMC3327632  PMID: 22429865
3.  Relation of a common variant of the adiponectin gene to serum adiponectin concentration and metabolic traits in an aged Japanese population 
Adiponectin is an adipocyte-derived protein that is down-regulated in obesity-linked disorders. Variants of the adiponectin gene (ADIPOQ) have been shown to affect adiponectin level. We have now examined the relation of polymorphisms of ADIPOQ to adiponectin concentration and to metabolic disorders in the Kita-Nagoya Genomic Epidemiology study, a population-based study of elderly Japanese. The genomic region including ADIPOQ was genotyped for 30 single nucleotide polymorphisms in 500 subjects of a screening population with the use of a fluorescence- or colorimetry-based allele-specific DNA primer–probe assay system. Four polymorphisms were then selected for genotyping in an additional 2797 subjects. Serum adiponectin level was negatively associated with metabolic abnormalities after adjustment for age and sex. The minor alleles of the rs1656930, Ile164Thr, and rs9882205 polymorphisms were associated with a low serum adiponectin level. Whereas the minor alleles of rs1656930 and rs9882205 were common (minor allele frequency of 6.2 and 38.5%, respectively), that of Ile164Thr was rare (0.9%). The minor allele of rs1656930 was positively associated with systolic blood pressure and the prevalence of hypertension. The association of rs1656930 with adiponectin level was replicated in an independent population. A subject with the 164Thr/Thr genotype had an extremely low serum adiponectin level (0.6 μg/ml) and the phenotype of metabolic syndrome. Our results suggest that a common variant of ADIPOQ, the minor allele of rs1656930, is associated with hypoadiponectinemia and hypertension. Screening for a common genetic background underlying low adiponectin levels might provide important information for assessment and management of metabolic disorders.
PMCID: PMC3062002  PMID: 21150884
adiponectin; polymorphism; metabolic disorder; hypertension; epidemiology
4.  Perinatal Loss of Nkx2-5 Results in Rapid Conduction and Contraction Defects 
Circulation research  2008;103(6):580-590.
Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming α-subunit (Nav1.5-α), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.
PMCID: PMC2590500  PMID: 18689573
conduction; contraction; gene targeting; transcription

Results 1-4 (4)