Topological isomers of human uroguanylin: interconversion between biologically active and inactive isomers

AbstractThe solution structures of the two compounds of human uroguanylin (I and II), which were generated during disulfide bond forming reaction, were found to be topological isomers by 1H-nuclear magnetic resonance spectroscopy. These isomers are interconvertible in aqueous media at rates which vary with the pH and temperature of the solution. Because compound I is active in the cGMP producing assay, but compound II is not, this interconversion may be useful for evaluating the activity of human uroguanylin both in vivo and in vitro

Association between white blood cell count and diabetes in relation to triglycerides-to-HDL cholesterol ratio in a Japanese population: The Nagasaki Islands study

Although our previous study found that diabetes combined with a high serum triglycerides to high-density lipoprotein cholesterol (TG-HDL) ratio constitutes a risk for atherosclerosis and chronic kidney disease (CKD), the association, in terms of TG-HDL ratio, between diabetes and white blood cell (WBC) count, which is an independent risk factor for atherosclerosis, has not been clarified. To investigate this association, we conducted a cross-sectional study of 3,998 Japanese subjects aged 30-89 years undergoing a general health check. We investigated the associations between WBC count and diabetes for all subjects, who were divided into tertiles according to TG-HDL level. Independent of classical cardiovascular risk factors, WBC count of both men and women was positively associated with diabetes combined with high but not with low TG-HDL. The multivariable odds ratios (ORs) and 95% confidence intervals (95%CIs) of 1SD (standard deviation) increment in WBC count (1,538/μL for men, 1,382/μL for women) for high TG-HDL diabetes and low TG-HDL diabetes were 1.39 (95%CI: 1.04-1.85) and 0.88 (95%CI: 0.66-1.19) for men, and 1.83 (95%CI: 1.45-2.33) and 0.91 (95%CI: 0.64-1.29) for women, respectively. In conclusion, for both men and women, WBC count is associated with high TG-HDL diabetes but not with low TG-HDL diabetes. These findings suggest that measuring WBC count is clinically relevant for estimating the risk of atherosclerosis and CKD in patients with diabetes categorized according to TG-HDL ratio

Hemoglobin as a response marker of endothelial cell damage in elderly nonoverweight non-anemic subjects.

　An independent positive correlation between hemoglobin level and risk of hypertension has been reported for non-anemicnon-overweight men and women. Additionally, serum hepatocyte growth factor (HGF) concentration in hypertensive subjects was reported to be significantly higher than in normotensive subjects. However no studies have reported on the correlation betweenhemoglobin and HGF. A cross-sectional study of 695 elderly non-overweight non-anemic Japanese subjects (231 men and 464 women; range 60-92 years old; Body mass index (BMI)<25kg/m2; Hemoglobin (Hb)?13g/dL for men and Hb?12g/dL for women) who were undergoing general health checkups in 2014 was conducted. Multiple linear regression analysis adjustment for classical cardiovascular risk factors showed a significant positive correlation between hemoglobin and serum HGF concentration(parameter estimate (β) =31.8, P<0.001) for men and (β=21.7, P<0.001) for women. An independent positive correlation between hemoglobin and HGF was observed in elderly non-anemic non-overweight Japanese subjects. Since HGF level may become elevated in response to endothelial cell damage (vascular remodeling), these findings suggest that measuring hemoglobin level is clinically relevant for estimating the response to endothelial cell damage

Body mass index and triglyceride-to-HDL-cholesterol ratio in relation to risk of diabetes: The Nagasaki Islands study

Body mass index (BMI) is well known as an independent risk factor for insulin resistance. In addition, lower BMI and lower insulin levels are recognized as specific characteristics of Asian diabetes patients. Since the triglyceride-to-HDL-cholesterol ratio (TG-HDL) is positively associated with insulin level, but inversely associated with insulin sensitivity, we supposed that diabetes combined with high but not with low TG-HDL might be positively associated with BMI. We therefore conducted a cross-sectional study of 2,431 Japanese subjects (905 men and 1,526 women) aged 30-79 years, who underwent a general health check, to investigate associations between BMI, diabetes and its subtypes that we defined on the basis of TG-HDL levels, which in turn were categorized according to sex-specific tertiles. Among the 172 diabetic patients identified in the study group, 45 showed low TG-HDL and 82 high TG-HDL. We found a significant inverse association between low-TG-HDL diabetes and BMI, and a significant positive association between high-TG-HDL diabetes and BMI. The multivariable-adjusted odds ratio and 95%CI for a 1SD increment in BMI (3.03 kg/m2 for men and 3.44 kg/m2 for women) for low-TG-HDL diabetes was 0.53 (95%CI: 0.36-0.77) and 1.57 (95%CI: 1.24-2.01) for high-TG-HDL diabetes. These findings demonstrated that for Japanese subjects associations between diabetes and BMI are strongly influenced by the TG-HDL status. Since a previous study of ours found that diabetes combined with high TG-HDL ratios constitutes a risk for atherosclerosis, these findings may serve as an effective tool for estimating risk of atherosclerosis for diabetes patients

Association between Alkaline Phosphatase and Anemia in Rural Japanese Men: The Nagasaki Islands study

Although bone metabolism is reportedly associated with production and maturation of blood corpuscles, and serum alkaline phosphatase (ALP) levels have been associated with bone metabolism, no published study has investigated the association between ALP and anemia. Furthermore, although ALP is known as an enzyme affected by alcohol consumption, there are no reports in the literature on associations between ALP and the risk of anemia in relation to drinking status. We conducted a cross-sectional study of 907 men aged 30-89 years undergoing a general health check-up to investigate the associations between ALP and anemia in relation to drinking status. Of the 907 participants, 120 men were diagnosed with anemia. The association between ALP and anemia was J-shaped. With the second quartile of ALP (194-228 IU/L) (Q2) as the reference group, the multivariable adjusted OR and 95%CI for anemia were 1.91 (95%CI: 0.96-3.82) for 277 IU/L (Q4). When the analysis was limited to non-drinkers, the associations became stronger with corresponding values of 3.34 (95%CI: 1.28-8.74), 3.18 (95%CI: 1.28-7.88) and 3.22 (95%CI:1.37-7.59). Not only lower but also higher levels of serum ALP are associated with anemia for men, especially non-drinkers. For analyses of associations between ALP and anemia, alcohol consumption should thus be considered a potential confounder

Associations of carotid atherosclerosis and hyperuricemia with height in relation to drinking status of rural Japanese men: The Nagasaki Islands study.

Background; Several studies have identified a positive, independent association between uric acid and atherosclerosis whereas uric acid was once considered to be a major antioxidant in human plasma with possible beneficial anti-atherosclerotic effects. Several other studies have found an inverse association between height and stroke, while a previous study of ours detected a positive association between height and hyperuricemia. However, even though uric acid levels may be strongly affected by alcohol consumption and serum creatinine, no published study has examined the possible associations between hyperuricemia and carotid atherosclerosis while taking both height and drinking status into account.Methods; We conducted a cross-sectional study of 1,337 men aged 30-89 years undergoing a general health check-up to investigate the associations of hyperuricemia and carotid atherosclerosis with height in relation to drinking status.Results; Of the total study population, 312 men were diagnosed with carotid atherosclerosis (carotid intima-media thickness (CIMT)?1.1 mm) and 365 men with hyperuricemia (serum uric acid>7.0mg/dL). For shorter non-drinkers, a significantly positive association between these two abnormalities was detected, which was independent of classical cardiovascular risk factors except for serum creatinine. However, this association ceased to exist after further adjustment for serum creatinine. However, while the age-adjusted model showed no significant association for taller drinkers, adjustment for serum creatinine produced a significantly inverse association.Conclusion; Our study established that hyperuricemia is associated with carotid atherosclerosis for Japanese men, while body height, drinking status and serum creatinine are important determining factors for this association

Causes of Abnormal Ca2+ Transients in Guinea Pig Pathophysiological Ventricular Muscle Revealed by Ca2+ and Action Potential Imaging at Cellular Level

BACKGROUND: Abnormal Ca(2+) transients are often observed in heart muscles under a variety of pathophysiological conditions including ventricular tachycardia. To clarify whether these abnormal Ca(2+) transients can be attributed to abnormal action potential generation or abnormal Ca(2+) handling/excitation-contraction (EC) coupling, we developed a procedure to determine Ca(2+) and action potential signals at the cellular level in isolated heart tissues. METHODOLOGY/PRINCIPAL FINDINGS: After loading ventricular papillary muscle with rhod-2 and di-4-ANEPPS, mono-wavelength fluorescence images from rhod-2 and ratiometric images of two wavelengths of emission from di-4-ANEPPS were sequentially obtained. To mimic the ventricular tachycardia, the ventricular muscles were field-stimulated in non-flowing Krebs solution which elicited abnormal Ca(2+) transients. For the failed and alternating Ca(2+) transient generation, there were two types of causes, i.e., failed or abnormal action potential generation and abnormal EC coupling. In cells showing delayed initiation of Ca(2+) transients with field stimulation, action potential onset was delayed and the rate of rise was slower than in healthy cells. Similar delayed onset was also observed in the presence of heptanol, an inhibitor of gap junction channels but having a non-specific channel blocking effect. A Na(+) channel blocker, on the other hand, reduced the rate of rise of the action potentials but did not result in desynchronization of the action potentials. The delayed onset of action potentials can be explained primarily by impaired gap junctions and partly by Na(+) channel inactivation. CONCLUSIONS/SIGNIFICANCE: Our results indicate that there are multiple patterns for the causes of abnormal Ca(2+) signals and that our methods are useful for investigating the physiology and pathophysiology of heart muscle

Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Background: Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation DK210 in cardiac troponinT. Methodology/Principal Findings: By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K + (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K + channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed

Association between alkaline phosphatase and hypertension in a rural Japanese population: The Nagasaki Islands study

Background: Although serum alkaline phosphatase (ALP) levels have been associated with hypertension, and ALP is known as an enzyme affected by alcohol consumption, no study has been published on the associations between ALP and the risk of hypertension in relation to drinking status.Methods: We conducted a cross-sectional study of 2,681 participants (837 men and 1,846 women) aged 30 to 89 years undergoing a general health check-up to investigate the associations between ALP and hypertension in relation to drinking status.Results: Of the 2,681 participants, 1,549 (514 men and 1,035 women) were diagnosed with hypertension. A sex difference was observed for the relationship between ALP and hypertension. While no significant association was observed for men, the association was significantly positive for women. The multivariable adjusted odds ratio and 95% coincidence interval (CI) of hypertension per increment of 1-log ALP were 0.95 (95% CI: 0.56 to 1.59) for men and 1.57 (95% CI: 1.07 to 2.33) for women. When this analysis was restricted to nondrinkers, a significantly elevated risk of hypertension was observed for men and remained significant for women; that is, 3.32 (95% CI: 1.38 to 8.02) for men and 1.68 (95% CI: 1.11 to 2.55) for women.Conclusion: ALP is associated with hypertension for both male and female nondrinkers, but not for drinkers. For analyses of associations between ALP and blood pressure, alcohol consumption should thus be considered a potential confounder