Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Identification and Analysis of a Novel NR0B1 Mutation in Late-Onset Adrenal Hypoplasia Congenita and Hypogonadism.

OBJECTIVE: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency and hypogonadotropic hypogonadism (HHG) caused by mutations of the NR0B1/DAX1 gene. We aimed to search for the presence of any NR0B1/DAX1 gene mutations in a referred patient and to further characterize the phenotypes of the identified mutation. CASE PRESENTATION: Herein, we report a Japanese patient with a novel missense mutation of the NR0B1/DAX1 gene resulting in adult-onset AHC and HHG. The patient was referred with diffuse skin pigmentation at 28 years of age, presented partial adrenal insufficiency and had undiagnosed incomplete HHG. Urological examination revealed severe oligospermia and testicular microlithiasis. RESULTS: The NR0B1/DAX1 gene mutation was identified by exome sequencing as a novel missense mutation (c.884A>T, p.Leu295His). We conducted in silico modeling of this mutant NR0B1/DAX1 protein (p.Leu295His) which affected the conserved hydrophobic core of the putative ligand-binding domain (LBD). In addition, functional analysis revealed that this mutant showed a decreased ability as a transcriptional repressor to suppress target genes, such as STAR and LHB. Furthermore, this mutant showed functionally impaired repression of steroidogenesis in human adrenocortical H295R cells. CONCLUSIONS: We identified a novel missense mutation of the NR0B1/DAX1 gene in a patient suffering from late-onset AHC and HHG, who presented with oligospermia and testicular microlithiasis. This mutant NR0B1/DAX1 protein was found to have reduced repressor activity, according to in vitro studies, clinically consistent with the patient's phenotypic features.

Temporal Trends in the Incidence and Clinical Features of Acute Myocardial Infarction in a Japanese Rural Area From 2006 to 2014.

BACKGROUND: Recent temporal trends in the incidence and clinical features of acute myocardial infarction (MI) in the Japanese population are not well known.Methods and Results:This study used comprehensive registration for first-ever MI during the 9-year period from 2006 to 2014 in a rural area of northeastern Japan. The study period was divided into three 3-year terms (T1, 2006-2008; T2, 2009-2011; T3, 2012-2014). During the study period, a total of 814 patients with MI were registered. Although the age-adjusted incidence rate (100,000 person-years) in the middle-aged group (<70 years) was relatively stable, the rate for the elderly group (≥70 years) in T3 was significantly lower than that in T1 in both men (368 vs. 279; P<0.01) and women (204 vs. 108; P<0.01). In the general population of the study area, the rate of prescribed anticholesterol drugs was significantly increased during the study period, especially in the elderly population (P<0.01). From a clinical perspective, although the performance rate of primary percutaneous coronary intervention significantly increased with a shortened duration of hospital stay, the in-hospital mortality rate, especially in the elderly, did not significantly decrease during the study period. CONCLUSIONS: The present study is the first to demonstrate a decreased age-adjusted incidence of MI during the period from 2006 to 2014 in a Japanese rural population, especially in the elderly.

Comparison between urine albumin-to-creatinine ratio and urine protein dipstick testing for prevalence and ability to predict the risk for chronic kidney disease in the general population (Iwate-KENCO study): a prospective community-based cohort study.

BACKGROUND: This study compared the combination of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) vs. eGFR and urine protein reagent strip testing to determine chronic kidney disease (CKD) prevalence, and each method's ability to predict the risk for cardiovascular events in the general Japanese population. METHODS: Baseline data including eGFR, UACR, and urine dipstick tests were obtained from the general population (n = 22 975). Dipstick test results (negative, trace, positive) were allocated to three levels of UACR (<30, 30-300, >300), respectively. In accordance with Kidney Disease Improving Global Outcomes CKD prognosis heat mapping, the cohort was classified into four risk grades (green: grade 1; yellow: grade 2; orange: grade 3, red: grade 4) based on baseline eGFR and UACR levels or dipstick tests. RESULTS: During the mean follow-up period of 5.6 years, 708 new onset cardiovascular events were recorded. For CKD identified by eGFR and dipstick testing (dipstick test ≥ trace and eGFR <60 mL/min/1.73 m(2)), the incidence of CKD was found to be 9 % in the general population. In comparison to non-CKD (grade 1), although cardiovascular risk was significantly higher in risk grades ≥3 (relative risk (RR) = 1.70; 95 % CI: 1.28-2.26), risk predictive ability was not significant in risk grade 2 (RR = 1.20; 95 % CI: 0.95-1.52). When CKD was defined by eGFR and UACR (UACR ≥30 mg/g Cr and eGFR <60 mL/min/1.73 m(2)), prevalence was found to be 29 %. Predictive ability in risk grade 2 (RR = 1.41; 95 % CI: 1.19-1.66) and risk grade ≥3 (RR = 1.76; 95 % CI: 1.37-2.28) were both significantly greater than for non-CKD. Reclassification analysis showed a significant improvement in risk predictive abilities when CKD risk grading was based on UACR rather than on dipstick testing in this population (p < 0.001). CONCLUSIONS: Although prevalence of CKD was higher when detected by UACR rather than urine dipstick testing, the predictive ability for cardiovascular events from UACR-based risk grading was superior to that of dipstick-based risk grading in the general population.

Elevated blood pressure at the first measurement predicts cardiovascular disease independently from the subsequent second reading in men, but not in women.

BACKGROUND AND METHODS: There have been no investigations concerning the association of each blood pressure (BP) reading with future cardiovascular disease (CVD) when multiple measurements are taken on one occasion. This community-based, prospective cohort study (n = 23 344, mean age = 62.4 years) investigated the associations between the BP obtained from the first and second of two consecutive measurements on one occasion and future cardiovascular events in men and women. RESULTS: During the mean follow-up of 5.5 years, 624 CVD events were identified. On the Cox regression analysis of age- and BP-adjusted models, the increased CVD risk of a hypertensive first measurement (systolic BP ≥ 140 mmHg) was independent from the second measurement in men. Even in subjects without a hypertensive second measurement, the CVD risk of the hypertensive first measurement was increased in men. In women, despite a hypertensive first measurement, subjects with a systolic BP < 130 mmHg on the second measurement showed a significantly reduced risk for CVD compared with subjects who retained a hypertensive level during the two measurements. CONCLUSIONS: An elevated BP on the first measurement should not be disregarded for CVD risk estimation in men, even if the second BP moves to the normal range. In women, elevated BP on the first measurement may have relatively less meaning for CVD prediction if the second BP shifts to a normal range.

Cardiovascular risk stratification with plasma B-type natriuretic peptide levels in a community-based hypertensive cohort.

Few reports have examined the utility of plasma B-type natriuretic peptide (BNP) testing for cardiovascular (CV) risk stratification in real-world hypertensive subjects. Subjects of the study were community-based hypertensive patients (n = 5,865). The CV event rate within each BNP quartile was estimated, and a Cox regression model was used to determine the relative hazard ratio (HR) among the quartiles. Furthermore, to determine the usefulness of BNP as a biomarker in combination with the Framingham risk score (FRS), the predictive abilities in terms of area under the curve of receiver operating characteristic analysis, net reclassification improvement, and integrated discrimination improvement indices were determined. The mean follow-up duration was 5.6 years. The highest quartile showed a significantly higher rate of CV events compared with the lower quartiles (p <0.001). After adjustment for established CV risk factors, the HR for CV events increased significantly according to the quartile (p value for trend <0.03), and the HR for the highest quartile was significantly elevated compared with the lowest quartile (HR 1.59, 95% confidence interval 1.16 to 2.19). The predictive abilities of BNP in terms of sensitivity and specificity for CV events were comparable with those of FRS. When BNP was added to an FRS-only model, the predictive abilities in terms of area under receiver operating characteristic curve, net reclassification improvement, and integrated discrimination improvement were significantly increased (all; p <0.001). Elevated BNP levels are thus a useful biomarker for CV risk stratification in unselected real-world hypertensive subjects. Adding BNP to an established CV risk score improves the predictive ability in this cohort.

Influence of mild-to-moderate alcohol consumption on cardiovascular diseases in men from the general population.

BACKGROUND AND METHODS: There is controversy about the association between mild-to-moderate alcohol consumption and a reduced risk of cardiovascular diseases. The relationships between daily alcohol consumption and the incidence of acute myocardial infarction (MI) or ischemic stroke (IS) were examined in men in a community-based, prospective cohort study (n = 8014, age 40-80 years, mean age = 64.1 years). Alcohol consumption was categorized into 3 groups (A1, none or occasional; A2, ≤25 g/day; A3, >25 g/day as ethanol) at baseline. RESULTS: During the mean follow-up of 5.5 years, 53 MIs and 186 ISs occurred. On Cox regression analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking index, and body mass index (BMI), the hazard ratio (HR) for incident MI was significantly lower in the A2 group than in the A1 group (HR = 0.49, p = 0.043). The HR for incident MI in the A3 group tended to be lower than in the A1 group (HR = 0.53, p = 0.10). In obese subjects, while a significantly lower HR for incident MI in the A2 group was retained (HR = 0.29, p = 0.049), no significant difference in the HR of the A3 group compared with the A1 group was found. No significant differences were found in the IS-free curve among the 3 groups of alcohol consumption. CONCLUSIONS: Alcohol consumption may have a protective effect on the onset of MI but not on IS in the general population. A U-shaped relation between alcohol consumption and incident MI was found in obese subjects. An appropriate limit for daily alcohol consumption, depending on the risk of ischemic heart disease, may need to be established.

Recurrent hypoglycemia during pregnancies in a woman with multiple autoantibodies including anti-insulin receptor antibody and anti-platelet antibody, whose serum lowered murine blood glucose levels and phosphorylated insulin receptor of CHO-IR cells.

We report a rare case of recurrent hypoglycemia in a pregnant woman during the period of pregnancies. She suffered from severe hypoglycemia and intrauterine fetal death during the first pregnancy. Thereafter, there was no hypoglycemia, and no obvious cause of hypoglycemia was found by close examinations. Two years later, at eight weeks into the second pregnancy, hypoglycemia recurred. The patient had multiple auto-antibodies including anti-insulin receptor antibody and anti-platelet antibody associated with decreased platelet count. She completed the pregnancy with continuous intravenous administration of glucose that prevented hypoglycemia and finally delivered a healthy baby by Caesarian section. Both the hypoglycemia and thrombocytopenia, and the auto-antibodies disappeared after the delivery. We analyzed the patient's serum as a possible cause of hypoglycemia. Administration of the serum lowered blood glucose levels of mice more strongly than control serum. In addition, the serum phosphorylated tyrosine of insulin receptor of Chinese hamster ovary cells overexpressing human insulin receptors (CHO-IR cells) in vitro. These results suggest that multiple auto-antibodies might have been induced by a trigger of pregnancy, although the precise mechanism was unclear, and the anti-insulin receptor antibody and anti-platelet antibody might have induced hypoglycemia and thrombocytopenia, respectively, during the pregnancy.

Systemic sclerosis presented as congestive heart failure: an autopsy case.

We report the autopsy results of a patient with systemic sclerosis with myositis lesions in the skeletal muscles and myocardium. A 69-year-old Japanese woman developed congestive heart failure and died due to respiratory failure with restrictive hypoventilation. The heart at autopsy showed dilated ventricular hypertrophy, and histopathology of the heart exhibited diffuse replacement fibrosis resembling the lesion of ischemic heart diseases in addition to patchy fibrosis around myocardial fibers suggesting post-myocarditis-like fibrosis.

Association of decreased variation of R-R interval and elevated serum C-reactive protein level in a general population in Japan.

Several studies have suggested that an increased high sensitivity C-reactive protein (hsCRP) level is a strong independent predictor of increased risk for atherosclerotic cardiovascular mortality and morbidity. Reduced heart rate variability (HRV) has also been reported to predict cardiovascular events such as sudden death and myocardial infarction in apparently healthy subjects. The aim of this cross-sectional study was to test the possible correlation between variation of the R-R interval as one of the markers of HRV and serum hsCRP levels in a general population in Japan. Resting, supine, 2-minute, beat-to-beat heart rate data were collected in 823 randomly selected participants enrolled in our cohort study. The coefficient of variation of the R-R interval (CVrr) was obtained as a parameter of HRV. To determine which factors predict the presence of low CVrr (below the 5 percentile) in this group, we performed a multivariate logistic regression analysis using cardiovascular risk factors and an elevated hsCRP level as independent variables. The lowest CVrr group showed significantly higher hsCRP levels compared to those of other quartiles (P < 0.01). After adjustment for confounding factors such as age, heart rate, obesity, hypercholesterolemia, and hypertension by multivariate logistic analysis, an elevated hsCRP level (OR = 3.11, 95%CI; 1.27-7.60: P < 0.02) was a significant independent predictor of low CVrr. The results of the present study indicate that an increased serum hsCRP level is significantly associated with reduced CVrr in this general population. It is conceivable that the parasympathetic nerve withdrawal and inflammation could interact with each other, resulting in the progression of atherosclerotic cardiovascular disease.

B-type natriuretic peptide testing for structural heart disease screening: a general population-based study.

BACKGROUND: Several types of structural heart disease are important precursors for congestive heart failure or cardioembolic stroke. We have previously demonstrated that plasma B-type natriuretic peptide (BNP) measurement is useful for detection of structural heart disease in a multiphasic health screening setting. To extend our hypothesis to the general population, the utility of BNP testing for identifying structural heart disease was assessed in a general population and in subgroups divided by sex, age, and presence/absence of risk factors. METHODS AND RESULTS: This cross-sectional cohort study measured plasma BNP concentrations in 993 randomly selected community-dwelling adults (mean age 58 years). All subjects underwent plasma BNP measurement and transthoracic echocardiography. Using prejudged criteria, 41 subjects were diagnosed to have some form of structural heart disease (mild left ventricular systolic dysfunction in 11, valvular heart disease in 9, hypertensive heart disease in 3, hypertrophic cardiomyopathy in 2, ischemic heart disease in 2, lone atrial fibrillation in 14). The utility of BNP testing was evaluated by receiver operating characteristic (ROC) analysis and by cost analysis for detection of 1 case within each subgroup of the cohort. Overall, the sensitivity and specificity of BNP testing for identification of structural heart disease were 61% and 92%, respectively. The area under the ROC curve was 0.77 (95% CI; 0.74-0.79). When sex-specific ROC analyses were performed, sensitivity and specificity were 61% and 91% in men, and 50% and 95% in women, respectively. Although the performance of BNP testing on the basis of these figures might be suboptimal, efficacy was improved in subgroups with a high prevalence of heart disease (>8%) such as the cohort aged > or =65 years (men, area under ROC curve = 0.88; cost

Plasma B-type natriuretic peptide levels and risk factors for congestive heart failure in a Japanese general population.

This cross-sectional study was performed to establish the rationale for BNP testing for identifying subjects at high risk of congestive heart failure (CHF) in a screening setting. Plasma BNP concentrations were measured in 8,178 community-dwelling residents (mean age, 62 +/- 12 years; 3,194 males). First, in order to determine age- and sex-related reference values for plasma BNP levels, subjects having factors known to influence plasma BNP levels were excluded. The remaining 3,410 subjects were eligible for the reference study. Second, to verify BNP testing for screening for subjects at high risk of CHF, the clinical characteristics of subjects showing abnormally high plasma BNP levels (> or = 97.5 percentile for each age- and sex-specific value of the reference cohort) were examined. In the reference subjects, plasma BNP levels increased with age in both genders, and were higher in women than in men. In the original cohort, age- and sex-specific reference values for high plasma BNP levels were related to the presence of major ECG abnormalities, hypertension, mildly elevated serum creatinine levels, and a history of coronary heart disease. The results of the present study indicate that individuals with high plasma BNP levels in the community have accumulating risk factors for CHF. This suggests that plasma BNP measurement may be a useful screening test for identification of individuals at high risk of CHF within a Japanese general population.

Association between serum C-reactive protein levels and pulse wave velocity: a population-based cross-sectional study in a general population.

Arterial stiffness as determined by aortic pulse wave velocity (PWV) has been shown to predict cardiovascular events in high-risk subjects such as those with hypertension or end-stage renal disease. Although it is suspected that low-grade inflammation as represented by increased C-reactive protein (CRP) plays an important role in the progression of atherosclerosis, it is not yet known whether serum CRP levels are associated with PWV. To examine the relationship between brachial-ankle PWV (baPWV) and serum CRP levels, several cardiovascular risk factors including these two markers (baPWV and CRP) were measured in 870 participants (mean age 59 years) randomly selected from a general population. Age, male gender, systolic blood pressure, heart rate, diabetes, and serum CRP levels increased with the quartiles divided by baPWV (all, p<0.01). By multiple regression analysis, age (p<0.001), systolic blood pressure (p<0.001), heart rate (p<0.001), body mass index (p<0.001), and CRP (p<0.01) were significant and independent predictors for baPWV. In conclusion, this cross sectional study has demonstrated in the general population that the arterial stiffness marker baPWV was independently correlated with serum CRP levels after adjustment for other established cardiovascular risks factors. This result suggests that baPWV may be a surrogate marker for atherosclerotic vascular damages including an inflammatory component.

Association between serum C-reactive protein levels and microalbuminuria: a population-based cross-sectional study in northern Iwate, Japan.

OBJECTIVE: The presence of microalbuminuria is a renal marker of vascular endothelial damage, and is an independent and strong predictor of increased risk for cardiovascular mortality and morbidity. Elevated circulating C-reactive protein (CRP) levels have recently been reported to be a novel cardiovascular risk factor, and it has been suggested that this acute-phase protein impairs vascular endothelial function. The aim of the present study was to determine whether serum CRP level is a dependent or an independent risk factor of microalbuminuria in the general population. METHODS: Subjects of this cross-sectional study were apparently healthy individuals drawn from the general Japanese population (mean age, 62; men, 2,236; women, 4,217). Serum CRP levels were determined using a highly sensitive kit and urine albumin-creatinine ratio (UACR) was calculated using a single urine sample. Multivariate logistic regression analysis was used to determine which risk factors (ie, age, hypertension, diabetes, obesity, hypercholesterolemia, smoking, and CRP) might predict the presence of microalbuminuria. RESULTS: In addition to classical cardiovascular risk factors such as age, hypertension, diabetes and obesity, serum CRP levels are also significantly correlated with microalbuminuria in men (odds ratio = 1.42, 95% CI = 1.13-1.79; p < 0.01) and women (odds ratio = 1.25, 95% CI = 1.05-1.49; p < 0.01). When subjects with diabetes were excluded from the analysis, serum CRP levels continued to be a significant predictor for microalbuminuria (odds ratio = 1.35, 95% CI = 1.06-1.73; p < 0.05 for men: odds ratio = 1.23, 95% CI = 1.03-1.47; p < 0.05 for women). CONCLUSIONS: The present study has shown that low-grade inflammation as represented by high sensitivity CRP levels may be significantly related to the presence of microalbuminuria. This suggests that microalbuminuria may be a useful marker representing systemic low-grade inflammation as well as being an established cardiovascular risk factor in apparently healthy individuals.

Effect of uni-adrenalectomy on blood pressure in a patient with excessive adrenal 18-hydroxy-11-deoxycorticosterone production bilaterally.

A 46-year-old woman was presented with mineralocorticoid excess syndrome and a large mass originating from the right adrenal gland. Clinical examination before right adrenalectomy revealed elevated serum concentrations of 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) both systemically and in the adrenal veins bilaterally. Histopathological and immunohistochemical analyses of the surgical specimen demonstrated adrenal hyperplasia of outer fasciculata cells, and the presence of cystic mass. The adrenalectomy ameliorated her blood pressure (BP) from 156/96 mmHg to 148/87 mmHg with a concomitant increase of serum potassium concentration from 3.1 mEq/l to 3.5 mEq/l. These results suggest that uni-adrenalectomy is, at least in part, effective in ameliorating not only BP but also potassium concentration in a patient of adrenal hyperplasia with excessive bilateral 18-OH-DOC production.