A longitudinal analysis of the progression from normal blood pressure to stage 2 hypertension: A 12-year Korean cohort.

BACKGROUND: The study aimed to estimate the incidence of and period of progression to stage 2 hypertension from normal blood pressure. METHODS: We selected a total of 21,172 normotensive individuals between 2003 and 2004 from the National Health Insurance Service-Health Screening and followed them up until 2015. The criteria for blood pressure were based on the American College of Cardiology/American Heart Association 2017 guideline (normal BP: SBP < 120 and DBP < 80 mmHg, elevated BP: SBP 120-129 and DBP < 80 mmHg, stage 1 hypertension: SBP 130-139 or DBP 80-89 mmHg, stage 2 hypertension: SBP ≥140 or DBP ≥ 90 mmHg). We classified the participants into four courses (Course A: normal BP → elevated BP → stage 1 hypertension→ stage 2 hypertension, Course B: normal BP → elevated BP → stage 2 hypertension, Course C: normal BP → stage 1 hypertension → stage 2 hypertension, Course D: normal BP → stage 2 hypertension) according to their progression from normal blood pressure to stage 2 hypertension. RESULTS: During the median 12.23 years of follow-up period, 52.8% (n= 11,168) and 23.6% (n=5004) of the participants had stage 1 and stage 2 hypertension, respectively. In particular, over 60 years old had a 2.8-fold higher incidence of stage 2 hypertension than 40-49 years old. After the follow-up period, 77.5% (n=3879) of participants with stage 2 hypertension were found to be course C (n= 2378) and D (n=1501). After the follow-up period, 77.5% (n=3879) of participants with stage 2 hypertension were found to be course C (n= 2378) and D (n=1501). The mean years of progression from normal blood pressure to stage 2 hypertension were 8.7±2.6 years (course A), 6.1±2.9 years (course B), 7.5±2.8 years (course C) and 3.2±2.0 years, respectively. CONCLUSIONS: This study found that the incidence of hypertension is associated with the progression at each stage. We suggest that the strategies necessary to prevent progression to stage 2 hypertension need to be set differently for each target course.

Phosphorescent blue organic light-emitting diodes with new bipolar host materials.

We report narrow band gap bipolar host materials, CbPr-3 (9,9'-[(3,3'-Biphenyl-3.3'-yl-bipyridine)-1,3-biphenyl]bis-9H-carbazole) and Bim-4 (9,9'-[5-(1-phenyl-1H-benzimadazol-2yl)-1,3-phenylene] bis-9H-carbazole), for blue phosphorescent OLEDs application. These two bipolar hosts have high triplet energy of > 2.9 eV, capable of reducing the driving voltages and improving efficiencies. Significant low driving voltages of 7.4 and 6.6 V were obtained for CbPr-3 and Bim-4 hosts, compared with 9.0 V of the commonly used host, mCP (1,3-bis(9-carbazolyl)benzene). At a given constant luminance of 1000 cd/m2, the power efficiency of both the bipolar host devices was enhanced by 2.5 times.

Incidence and risk factors of vascular complications in people with impaired fasting glucose: a national cohort study in Korea.

This study aimed to evaluate the risk of vascular complications of impaired fasting glucose (IFG). This population-based study included 425,608 participants from the National Health Screening Cohort in Korea in 2003 and 2004 who were followed-up until 2015. The participants were classified into normal, IFG, and diabetes groups based on fasting plasma glucose levels. Incidence rate (per 1000 person-year) was evaluated for the following vascular complications: cardiovascular (ischemic heart disease, cerebrovascular disease, arterial and capillary disease), renal, and retinal diseases. Hazard ratios (HR) of IFG for diabetes were estimated after adjusting for patient characteristics. Among the 88,330 IFG participants, the incidence of cardiovascular, chronic renal and retinal diseases were 11.52, 0.47, and 1.08 per 1000 person-years, respectively. Furthermore, IFG patients with a family history of diabetes, past history of hypertension, and high body mass index had significantly increased risk of vascular complications [adjusted HR, cardiovascular: 1.39 (95% CI 1.33-1.46); renal: 2.17 (95% CI 1.66-2.83); and retinal: 1.14 (95% CI 0.98-1.32)]. IFG patients have a substantial risk of cardiovascular, chronic renal and retinal diseases. Therefore, early preventative interventions are beneficial, especially for those with high-risk factors, in whom should emphasize on maintaining a healthy lifestyle, early screening and continuous follow-up.

Incidence and risk factors for progression from prehypertension to hypertension: a 12-year Korean Cohort Study.

OBJECTIVES: This study evaluated the incidence and risk factors for progression from prehypertension to hypertension among middle-aged and elderly Korean adults. METHODS: A total of 115 456 participants with prehypertension in 2003-2004 were selected from the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) Program. All participants were followed until 2015. Potential risk factors for progression to hypertension were evaluated using the chi-squared test or t-test. A Cox proportional hazards model was used to predict the risk of progression to hypertension according to sex. The incidence of hypertension in the prehypertension group was evaluated by calculating the incidence density during the entire follow-up period. RESULTS: During the follow-up period, 48 919 participants experienced progression to hypertension, which corresponded to incidence densities of 45.82/1000 person-years among men and 53.57/1000 person-years among women. Among both men and women, progression to hypertension was predicted by an elevated BMI, family history of hypertension, history of diabetes mellitus, and older age. Among men, progression to hypertension was associated with frequent drinking and high alanine aminotransferase levels. Among women, progression to hypertension was associated with high hemoglobin levels and low household income. CONCLUSION: This study identified various risk factors for progression from prehypertension to hypertension among middle-aged and elderly Korean adults. This information may help researchers develop comprehensive and effective strategies for managing prehypertension.

Risk factors of the progression to hypertension and characteristics of natural history during progression: A national cohort study.

BACKGROUND: Although the high disease burden that results from cardiovascular complications of hypertension, factors related to the progression to hypertension in the normotensive population are not actively reported. The purpose of this study was to estimate the rate of the progression to hypertension and to reveal the associated risk factors. METHODS: The study included normotensive participants from the National Health Insurance Service-National Health Screening Cohort, and contained a 10% sample of all adults who received a national health screening test in either 2002 or 2003. At the end of the study in 2015, the patients were divided into two groups based on whether or not they progressed to hypertension. Cox proportional hazard modeling was performed to identify risk factors for progression. Subgroup analysis using logistic regression was employed to reveal factors influencing the different natural history of the progression. RESULTS: Among the 75,335 included participants, the progression rate to hypertension was 66.39% (50,013), with an adjusted incidence rate of 8.62 per 100 person-year in the aged 40-64 group and 12.68 in the aged 65 or above group. Age, BMI, hemoglobin, and family history of hypertension and other diseases were related to the progression. Among the progression group, 78.21% (39,116) participants skipped a pre-hypertensive status; this group consisted of older females with lower pulse pressure and more alcohol consumption compared to people who had pre-hypertensive status before the progression. CONCLUSION: Substantial risk factors for the progression to hypertension should be carefully managed even in normotensive participants who receive health screening tests.

Isoeleutherin and eleutherinol, naturally occurring selective modulators of Th cell-mediated immune responses.

Natural compounds possessing naphthopyran moiety have been attracted by their anti-bacterial, anti-fungal, and anti-viral activities, as well as anti-tumor activities. Although chemical structures were critical for the potential biological activities, the detailed functional mechanisms remained unclear. Here, we have studied the effects of naphthopyran derivatives (eleutherin, isoeleutherin, and eleutherinol) on T helper cell-mediated immune responses to understand the mechanisms of their anti-microbial and anti-tumor activities. The study revealed that isoeleutherin, which has 1,4-naphthoquinone ring with alpha-methyl group, selectively and specifically stimulated IFNgamma production through the activation of T-bet gene transcription, thus enhancing Th1-mediated immune responses. However, a natural naphthopyran-4-one, eleutherinol dramatically inhibited both IFNgamma and IL-2 productions during Th cell activation by suppressing the gene transcriptions of cytokines. Therefore, we suggest that the chemical modification and chirality of naphthopyran moiety in isoeleutherin and eleutherinol may be critical for the selective modulation of T helper cell-mediated immune responses.

Characterization of human monoclonal autoantibody Fab fragments against oxidized LDL.

Oxidized low-density lipoprotein (oxLDL) is a key autoantigen in atherosclerosis. The genetic structures and pathogenic roles of autoantibodies against this protein remain to be established. In this study, we cloned several monoclonal IgG autoantibody Fab fragments specific for oxLDL from peripheral blood lymphocytes of atherosclerosis patients, using phage display technology. The sequences of their variable regions were determined at the cDNA level. The closest germline counterparts for the heavy chains belonged to the V(H)3 or V(H)1 family. The sequences and lengths of complementarity-determining regions (CDR)3-V(H) were diverse, and frequent mutations of positively charged amino acids (particularly arginine) over entire V(H) and V(L) sequences were observed. It is proposed that anti-oxLDL autoantibody formation is driven by antigens. Among the Fabs, P2-8 and P3-175 bound to both MDA-LDL and Cu-oxLDL, and inhibited the uptake of oxLDL by macrophages, suggesting the epitope(s) recognized by the Fabs is a part of ligands on oxLDL that is involved in uptake by macrophage scavenger receptor. These human autoantibody Fabs require detailed investigation to ascertain their potential as agents for clinical applications.

Effect of naturally occurring hydroxychavicol acetate on the cytokine production in T helper cells.

Naturally occurring phenolic compounds, such as chavicol analogues, have been shown to have potent antioxidant and anti-inflammatory activities. We have previously isolated two chavicol acetate analogues, acetoxychavicol acetate (ACA) and hydroxychavicol acetate (HCA) from the rhizomes of Alpinia galanga. Although the function of ACA has been studied in many systems, the function of HCA has yet to be systemically examined. In this study, we have comparably examined the functions of ACA and HCA on the cytokine production in Th cells. ACA exhibited potent antioxidant activity and increased cell apoptosis; therefore, cytokine production by Th cells was diminished. Although HCA had neither antioxidant activity nor pro-apoptotic function, it was shown to increase IL-2 production and attenuate IFNgamma expression in Th cells. In addition, we demonstrated that HCA suppressed T-bet expression, which is responsible for IL-2 suppression and IFNgamma induction in Th cells and inhibited T-bet-mediated Th1 cell differentiation. Therefore, we suggest that HCA may be beneficial as therapeutics for treating inflammatory immune disorders caused by extravagant activation of Th1-mediated immune responses.

Regulatory mechanisms of IL-2 and IFNgamma suppression by quercetin in T helper cells.

Quercetin is a popular flavonoid compound that is biosynthesized by plants; it is suggested to modulate a variety of inflammatory responses of macrophages and T lymphocytes. Oral administration of quercetin in arthritic rats dramatically diminishes clinical signs of arthritis. Moreover, quercetin ameliorates experimental autoimmune encephalomyelitis, which is associated with Th1-mediated immune responses. Like quercetin inhibits macrophage-induced cytokine production, it also blocks IL-12-dependent JAK-STAT signaling in Th cells. Despite the anti-inflammatory effects of quercetin acting through Th cells, the regulatory mechanisms remain unclear. Here, we studied the function of quercetin in Th cells and found that quercetin suppressed both IFNgamma and IL-2 production upon T cell receptor stimulation. Furthermore, we uncovered the regulatory mechanisms of quercetin involved in the inhibition of cytokine production during Th cell activation. The fact that quercetin-derived IFNgamma suppression was blocked in T-bet-deficient Th cells demonstrated quercetin act through the modulation of T-bet expression. Whereas IL-2 inhibition by quercetin was independent of T-bet expression, quercetin diminished IL-2R alpha expression, which is critical for positive regulatory loop of IL-2 autoactivation. Taken together, quercetin is suggested to repress both IFNgamma and IL-2 cytokine production by independent mechanisms; T-bet-dependent IFNgamma suppression and IL-2R alpha-dependent IL-2 inhibition.

The impact of gender on progression of renal disease: potential role of estrogen-mediated vascular endothelial growth factor regulation and vascular protection.

Male gender is associated with a more rapid progression of renal disease independent of blood pressure, dietary protein intake, or serum lipid levels. Recently, we reported a key role for the intrarenal vasculature in progressive renal disease (Kang D-H, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of endothelium in progressive renal disease. J Am Soc Nephrol 2002, 13:806-816). We hypothesized that estrogen-mediated preservation of the renal vasculature could account for the better renal outcome in female rats. We analyzed micro- and macrovascular changes in the 5/6 remnant kidney (RK) models both in male (n = 24) and female (n = 24) Sprague-Dawley rats up to 12 weeks after renal mass reduction. At 12 weeks, male and female RK rats had equivalent blood pressure, glomerular tuft area, and RK/body weight, but male rats showed worse renal function, proteinuria, glomerulosclerosis (%), and tubulointerstitial fibrosis. At 12 weeks peritubular capillary (PTC) EC proliferation and PTC density were higher in female RK rats whereas macrovascular changes in preglomerular vessels (smooth muscle cell proliferation, medial wall thickening, and adventitial fibrosis) were less prominent. The expression of vascular endothelial growth factor (VEGF) and VEGF type 2 receptor (flk-1) in renal cortex assessed by immunostaining were higher in female RK rats. To dissect the mechanism of sex hormone-induced vascular remodeling and VEGF regulation, we investigated the in vitro effect of 17 beta-estradiol (17 beta E, 10 nmol/L) on proliferation and VEGF expression of renal tubular cells (rat proximal tubular cells), vascular smooth muscle cells (VSMCs), and human umbilical vein endothelial cells (HUVECs). 17 beta E directly stimulated the proliferation of HUVECs, whereas it inhibited serum-induced proliferation of VSMCs. 17 beta E stimulated VEGF mRNA expression both in renal tubular cells and VSMCs. However, when cells were pretreated with a nitric oxide donor to simulate the in vivo condition, 17 beta E inhibited VEGF mRNA expression and protein release in VSMCs. In conclusion, female RK rats developed less glomerulosclerosis and renal failure compared to male RK rats in association with greater preservation of PTC and less preglomerular arteriopathy. Estrogen stimulated basal VEGF expression in renal tubular cells. We propose that estrogen may protect female rats in progressive renal disease by stimulating VEGF expression and maintaining a healthy intrarenal vasculature.

Pilot study of mass screening for Wilson's disease in Korea.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism with copper accumulation in the liver as well as in the central nervous system. Treatment of WD includes oral chelating agents and diet and it is effective. However, once irreversible damage has occurred, the effect of treatment is diminished and the patient's quality of life is compromised. It is estimated that at least half of the patients with WD remain undiagnosed and die of untreated disease. Early detection of patients presymptomatically has been hampered by the lack of effective methods for mass screening. Recently, a sandwich ELISA method for ceruloplasmin measurement in blood spots was developed. We have used this method to analyze blood specimens collected on filter paper from 3667 children aged 3 months-15 years. The mean value of ceruloplasmin was 30.5+/-9.5 mg/dL. Among these children, we identified one WD case, a 32-month-old boy with markedly reduced ceruloplasmin concentration (2.3 mg/dL). Measurement of CP level in dried blood spot sample is proposed as a reliable method for population screening of WD.