The association between clinically diagnosed insomnia and age-related macular degeneration: a population-based cohort study.

PURPOSE: The decreased level of melatonin, the substance involved in the control of the sleep-wake cycle, has been reported among the patients with age-related macular degeneration (AMD). However, knowledge about the relationship between sleep disturbance and AMD is still limited. This longitudinal case-control study aims to investigate the risk of incident AMD among the patients with clinically diagnosed insomnia using the Taiwan National Health Insurance Research Database. METHODS: The insomnia cohort (n = 15 465) consisted of newly diagnosed insomnia cases aged ≥55 years between 2000 and 2009. Subjects without insomnia, matched for age, gender and enrolment time, were randomly sampled as the control cohort (n = 92 790). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of incident AMD for the two cohorts after adjusting for potential confounders. RESULTS: Of the 108 255 sampled subjects, 2094 (1.9%) were diagnosed with AMD, including 214 (0.2%) with neovascular AMD, during a mean follow-up period of 5.1 ± 2.8 years. Insomnia patients were more likely to have subsequent AMD than those without insomnia (2.5% versus 1.8%, p < 0.001). Further, the incidence of exudative AMD was also higher in the insomnia cohort than the control cohort (0.3% versus 0.2%, p = 0.002). The adjusted HR was 1.33 (95% confidence interval [CI], 1.18-1.48, p < 0.001) for AMD and 1.67 (95% CI, 1.20-2.33, p = 0.002) for exudative AMD. CONCLUSIONS: Clinically diagnosed insomnia is an independent indicator for the increased risk of subsequent AMD development.

Activation of heme oxygenase-1 by Ginkgo biloba extract differentially modulates endothelial and smooth muscle-like progenitor cells for vascular repair.

Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.

High Incidence of Secondary Hyperparathyroidism in Bariatric Patients: Comparing Different Procedures.

BACKGROUND: Bariatric surgery is an effective therapy for morbid obesity but may reduce calcium absorption and significantly decrease the bone mineral density. This study examined the prevalence of secondary hyperparathyroidism (SHPT) in obese subjects during follow-up after different bariatric surgeries. We investigated predictors of SHPT. METHODS: We enrolled 1470 obese subjects undergoing bariatric/metabolic surgery with at least 1-year follow-up, including 322 patients undergoing Roux-en-Y gastric bypass (RYGB), 695 undergoing single anastomosis (mini-) gastric bypass (SAGB), 93 undergoing laparoscopic adjustable gastric banding (LAGB), and 360 undergoing sleeve gastrectomy (SG). Five years of data were available for 215 patients. Patients were instructed to supplement their diet according to the guideline. Calcium, parathyroid hormone (PTH), and vitamin D levels were measured before surgery and at 1 and 5 years after surgery. SHPT was defined as PTH > 69 pg/mL. RESULTS: The overall prevalence of SHPT was high, 21.0% before surgery and was not different between patients with different bariatric procedures. Pre-operative PTH correlated with age, BMI, and vitamin D levels. Multi-variate analysis confirmed that vitamin D level was the only independent predictor of SHPT before surgery. The prevalence of SHPT increased to 35.4% at 1 year after surgery and 63.3% at 5 years after surgery. SAGB had the highest prevalence of SHPT (50.6%) followed by RYGB (33.2%), LAGB (25.8%), and SG (17.8%) at 1 year after surgery. At 5 years after surgery, SAGB still had the highest prevalence of SHPT (73.6%), followed by RYGB (56.6%), LAGB (38.5%), and SG (41.7%). Serum PTH at 1 year after surgery correlated with decreased BMI and weight loss. Multi-variate analysis confirmed that age, sex, calcium level, and bypass procedure were independent predictor of SHPT after surgery. CONCLUSIONS: The prevalence of SHPT is high in morbidly obese patients before bariatric surgery which is related to vitamin D deficiency. The prevalence of SHPT increased continually along with the time after bariatric surgery, especially in patients receiving SAGB, followed by RYGB. The supplementation of vitamin D and calcium have to be higher in bypass procedure, especially in malabsorptive procedure.

Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease.

BACKGROUND: Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. OBJECTIVES: We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. METHODS: Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. RESULTS: The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. CONCLUSION: This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease.

The Association Between Insomnia and Increased Future Cardiovascular Events: A Nationwide Population-Based Study.

OBJECTIVES: Insomnia may increase the risk of cardiovascular disease (CVD), but the reported magnitude of the associations between sleep characteristics and CVD is inconsistent. We investigated the association between insomnia and the risk of developing acute myocardial infarction (AMI) and/or stroke by using a nationwide, population-based cohort database in Taiwan. METHODS: The analyses were conducted using information from a random sample of 1 million people enrolled in the nationally representative Taiwan National Health Insurance Research Database. A total of 44,080 individuals who were 20 years or older, including 22,040 people who had diagnosis of insomnia during the study period and an age-, sex-, comorbidity-matched group of 22,040 people without insomnia, were enrolled in our study. The study end points were the occurrence of cardiovascular events including AMI or stroke during follow-up. RESULTS: During a 10-year follow-up, 302 AMI events and 1049 stroke events were identified. The insomnia group had a higher incidence of AMI (2.25 versus 1.08 per 1000 person-years) and stroke (8.01 versus 3.69 per 1000 person-years, p < .001). Cox proportional hazard regression model analysis showed that insomnia was independently associated with a higher risk of future AMI (hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.31-2.16, p < .001), stroke (HR = 1.85, 95% CI = 1.62-2.12, p < .001), and the composite event index (HR = 1.81, 95% CI = 1.61-2.05, p < .001), after adjusting for age, sex, and comorbidities. CONCLUSIONS: Insomnia is associated with an increased risk of future cardiovascular events.

Effects of pitavastatin versus atorvastatin on the peripheral endothelial progenitor cells and vascular endothelial growth factor in high-risk patients: a pilot prospective, double-blind, randomized study.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) reflect endothelial repair capacity and may be a significant marker for the clinical outcomes of cardiovascular disease. While some high-dose statin treatments may improve endothelial function, it is not known whether different statins may have similar effects on EPCs.This study aimed to investigate the potential class effects of different statin treatment including pitavastatin and atorvastatin on circulating EPCs in clinical setting. METHODS: A pilot prospective, double-blind, randomized study was conducted to evaluate the ordinary dose of pitavastatin (2 mg daily) or atorvastatin (10 mg daily) treatment for 12 weeks on circulating EPCs in patients with cardiovascular risk such as hypercholesterolemia and type 2 diabetes mellitus (T2DM). Additional in vitro study was conducted to clarify the direct effects of both statins on EPCs from the patients. RESULTS: A total of 26 patients (19 with T2DM) completed the study. While the lipid-lowering effects were similar in both treatments, the counts of circulating CD34+KDR+EPCs were significantly increased (from 0.021 ± 0.015 to 0.054 ± 0.044% of gated mononuclear cells, P < 0.05) only by pitavastatin treatment. Besides, plasma asymmetric dimethylarginine level was reduced (from 0.68 ± 0.10 to 0.53 ± 0.12 µmol/L, P < 0.05) by atorvastatin, and plasma vascular endothelial growth factor (VEGF) level was increased (from 74.33 ± 32.26 to 98.65 ± 46.64 pg/mL, P < 0.05) by pitavastatin. In the in vitro study, while both statins increased endothelial nitric oxide synthase (eNOS) expression, only pitavastatin increased the phosphorylation of eNOS in EPCs. Pitavastatin but not atorvastatin ameliorated the adhesion ability of early EPCs and the migration and tube formation capacities of late EPCs. CONCLUSIONS: While both statins similarly reduced plasma lipids, only pitavastatin increased plasma VEGF level and circulating EPCs in high-risk patients, which is probably related to the differential pleiotropic effects of different statins. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov, NCT01386853.

Risk of central serous chorioretinopathy in adults prescribed oral corticosteroids: a population-based study in Taiwan.

PURPOSE: To investigate the incidence and risk factors for central serous chorioretinopathy (CSCR) in adults who use oral corticosteroids in Taiwan. METHODS: This is a population-based nested case-control study between 2000 and 2008. From the Taiwan National Health Insurance Research Database, adults who were repetitively prescribed oral corticosteroids were included as the study cohort. Of those, newly diagnosed CSCR cases were identified and the CSCR incidence was calculated. Subjects matched for age, gender, and the enrollment time were randomly selected as the controls. Corticosteroids use was compared between the cases and controls. Poisson and conditional logistic regressions were used to analyze the potential risk factors for CSCR. RESULTS: Among 142,035 oral corticosteroids users, 320 cases of CSCR were identified, and 1,554 matched controls were randomly selected. The incidence rate of CSCR was 44.4 (95% confidence interval, 39.5-49.3) cases per 100,000 person-years. Multivariate Poisson regression showed that male patients and those aged 35 years to 44 years had significantly higher incidence rates of CSCR. There were no differences in either median dosage or mean duration of systemic corticosteroid treatment between the cases and controls. After adjusting for other confounders, current use of oral corticosteroids was found to be significantly associated with the risk of CSCR (odds ratio, 2.40; 95% confidence interval, 1.49-3.89). CONCLUSION: Male gender, middle age, and current use of oral corticosteroids were found to be the risk factors for CSCR. However, oral corticosteroids dosage and treatment duration were not associated with the CSCR risk.

Ginkgo biloba extract reduces high-glucose-induced endothelial reactive oxygen species generation and cell adhesion molecule expression by enhancing HO-1 expression via Akt/eNOS and p38 MAP kinase pathways.

AIM: Hyperglycemia is one of the major risk factors leading to vascular complications in clinical diabetes mellitus. Ginkgo biloba extract (GBE), an antioxidant herbal medicine, possesses anti-inflammatory effects. We examined whether GBE can reduce high glucose-induced endothelial adhesiveness to monocytes, an in vitro sign mimicking in vivo early atherogenesis, through selective regulation of heme oxygenase (HO)-1 expression. METHODS: Human aortic endothelial cells (HAECs) were cultured with normal glucose or high glucose (25 mM) for 4 days and subsequently combined with GBE (EGb761, Dr. Willmar Schwabe, Karlsruhe, Germany) treatment in the last 18 h of the 4-day period. The endothelial reactive oxygen species (ROS) generation, adhesion molecule expression and the adhesiveness to monocytes were examined. The specific signal pathways such as HO-1 were also examined. RESULTS: High glucose increased ROS generation, adhesion molecule expression and the adhesiveness to monocytes in HAECs. These high glucose-induced phenomena could be suppressed by GBE (100 µg/ml)-induced HO-1 expression in a dose-dependent and time-dependent manner. In addition, jun N-terminal kinases inhibitor or phosphoinositide 3 kinase inhibitor could reduce GBE-induced HO-1 expression. Furthermore, HO-1 inhibitor, HO-1 siRNA, endothelial nitric oxide synthase (eNOS) siRNA, or nuclear factor erythroid 2-related factor (Nrf) 2 siRNA blocked the cytoprotective effects of GBE. Meanwhile, p38/mitogen-activated protein kinase (MAPK) inhibitor could also reduce the effects of GBE on HO-1 induction. CONCLUSION: GBE could reduce high glucose-induced endothelial adhesion via enhancing HO-1 expression through the Akt/eNOS and p38/MAPK pathways. Our findings suggest a potential strategy targeting on HO-1 induction by GBE for endothelial protection in the presence of high glucose such as that in diabetes mellitus.

Increased risk of erectile dysfunction among males with central serous chorioretinopathy -- a retrospective cohort study.

PURPOSE: Central serous chorioretinopathy (CSCR) mostly affects middle-aged men and has been associated with stress and hypercortisolism. We hypothesized that some factors prone to inducing CSCR could also have a harmful effect on erectile function. This study aimed to investigate the risk of subsequent erectile dysfunction after CSCR using Taiwan National Health Insurance Research Database. METHODS: The study cohort (n = 1220) consisted of newly diagnosed CSCR men aged 19-64 years between 1999 and 2007, and men matched for age, monthly income and time of enrolment were randomly selected as the control group (n = 10870). Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of clinically diagnosed erectile dysfunction (including organic origin and/or psychogenic origin) for the two groups. Erectile dysfunction-free survival analysis was assessed using a Kaplan-Meier method. RESULTS: Twenty-five patients (2.0%) from the CSCR cohort and 103 (0.9%) from the control group were diagnosed erectile dysfunction clinically during a mean observation period of 4.3 years. Patients with CSCR had a significantly higher incidence of erectile dysfunction diagnosis than those without CSCR (p < 0.001). After adjusting for age, geographic location, chronic comorbidities and medication habits, patients with CSCR were found to have a 2.22-fold [95% confidence interval (CI), 1.42-3.46] higher hazard ratio of a subsequent erectile dysfunction diagnosis than the matched controls. The adjusted HR for organic and psychogenic erectile dysfunction were 2.14 (95% CI: 1.34-3.44) and 3.83 (95% CI: 1.47-10.01), respectively. CONCLUSIONS: Central serous chorioretinopathy was independently associated with an increased risk of being diagnosed with erectile dysfunction.

Angiotensin-receptor blockers and risk of Alzheimer's disease in hypertension population--a nationwide cohort study.

BACKGROUND: Although emerging evidence shows angiotensin-receptor blockers (ARBs) may have a beneficial effect against Alzheimer's disease (AD), the association is not consistent. We investigated the association between ARB use and the risk of development of AD using a nationwide, population-based cohort database in Taiwan. METHODS AND RESULTS: In total, 16,426 newly diagnosed hypertensive patients who were administered ARB without a previous diagnosis of AD were identified from the Taiwan National Health Insurance database. The comparison group consisted of hypertensive patients who did not receive ARB, and were matched to exposed individuals using propensity score by enrolled time, age, sex, and comorbidities. During an average of 5.24 ± 2.01 years of follow-up, a total of 1,031 cases (3.13%) of new AD occurred. The log-rank test showed no significant difference in the AD occurrence rate between subjects exposed to ARBs and non-exposed controls [488 (2.97%) vs. 543 (3.29%), P=0.221]. After adjusting for age, sex, comorbidities, and medications, only advanced age [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.12-1.13, P<0.001), female sex (HR 1.18, 95% CI 1.04-1.33, P=0.011), diabetes (HR 1.53, 95% CI 1.31-1.79, P<0.001), but not ARB (HR 1.08, 95% CI 0.96-1.22, P=0.222) were independently associated with AD development. CONCLUSIONS: The use of ARB was not significantly associated with a reduction of risk of AD in Asian patients with essential hypertension.

Low-dose dextromethorphan, a NADPH oxidase inhibitor, reduces blood pressure and enhances vascular protection in experimental hypertension.

BACKGROUND: Vascular oxidative stress may be increased with age and aggravate endothelial dysfunction and vascular injury in hypertension. This study aimed to investigate the effects of dextromethorphan (DM), a NADPH oxidase inhibitor, either alone or in combination treatment, on blood pressure (BP) and vascular protection in aged spontaneous hypertensive rats (SHRs). METHODOLOGY/PRINCIPAL FINDINGS: Eighteen-week-old WKY rats and SHRs were housed for 2 weeks. SHRs were randomly assigned to one of the 12 groups: untreated; DM monotherapy with 1, 5 or 25 mg/kg/day; amlodipine (AM, a calcium channel blocker) monotherapy with 1 or 5 mg/kg/day; and combination therapy of DM 1, 5 or 25 mg/kg/day with AM 1 or 5 mg/kg/day individually for 4 weeks. The in vitro effects of DM were also examined. In SHRs, AM monotherapy dose-dependently reduced arterial systolic BP. DM in various doses significantly and similarly reduced arterial systolic BP. Combination of DM with AM gave additive effects on BP reduction. DM, either alone or in combination with AM, improved aortic endothelial function indicated by ex vivo acetylcholine-induced relaxation. The combination of low-dose DM with AM gave most significant inhibition on aortic wall thickness in SHRs. Plasma total antioxidant status was significantly increased by all the therapies except for the combination of high-dose DM with high-dose AM. Serum nitrite and nitrate level was significantly reduced by AM but not by DM or the combination of DM with AM. Furthermore, in vitro treatment with DM reduced angiotensin II-induced reactive oxygen species and NADPH oxidase activation in human aortic endothelial cells. CONCLUSIONS/SIGNIFICANCE: Treatment of DM reduced BP and enhanced vascular protection probably by inhibiting vascular NADPH oxidase in aged hypertensive animals with or without AM treatment. It provides the potential rationale to a novel combination treatment with low-dose DM and AM in clinical hypertension.

Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways.

BACKGROUND: Chronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation. MATERIALS AND METHODS: Human aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated. RESULTS: Either high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes. CONCLUSIONS: Long-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.

Statin use and hospitalization in patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study in Taiwan.

BACKGROUND: Statins have been widely prescribed to treat hyperlipidemia, and can be used for primary and secondary prevention of cardiovascular diseases. Several studies have shown that statins have antiinflammatory effects in addition to cholesterol-lowering properties. There is new evidence suggesting that statins have beneficial effects on patients with chronic obstructive pulmonary disease (COPD), which is characterized by a persistent inflammatory response. OBJECTIVE: The aim of this study was to determine the association between statins and COPD by using the Taiwan National Health Insurance database. METHODS: This was a nationwide population-based cohort study. A total of 6252 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who received statins for hyperlipidemia treatment were identified from the 1 million sampling cohort dataset between January 2000 and December 2007. Another 12,469 newly diagnosed COPD patients (median age, 64 years; 50.3% male) who were matched for age, gender, and medication for COPD treatment, except for statin use, were enrolled as the control group. The end point of the study was hospitalization due to COPD. RESULTS: During an average of 4.58 (2.36) years' follow-up period, there were 1832 patients who experienced hospitalization for COPD exacerbation (statin vs control = 508 [8.1%] vs 1324 [10.6%]; P = 0.001). Statin use was independently associated with the decreased risk of COPD hospitalization (hazard ratio, 0.66; 95% CI, 0.60-0.74; P < 0.001). CONCLUSIONS: In the selected Taiwanese population, statins were associated with reduced hospitalization due to COPD in patients newly diagnosed with COPD, suggesting a potential beneficial effect of statins in patients with COPD.

Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis.

CONTEXT: Primary aldosteronism (PA) is associated with a higher incidence of cardiovascular events, probably through mineralocorticoid receptor (MR)-dependent endothelial cell dysfunction, in comparison with essential hypertension (EH). OBJECTIVE: Our objective was to investigate the number and function of endothelial progenitor cells (EPC) in PA and the relationship with arterial stiffness and disease progression. DESIGN AND SETTING: We conducted a prospective study of the change of EPC number and outcome of PA patients after treatment at a tertiary medical center. PRIMARY OUTCOMES: Changes in arterial stiffness and EPC number after treatment and the curability of hypertension were assessed. PATIENTS: A total of 113 PA patients (87 patients diagnosed with aldosterone-producing adenoma, 26 with idiopathic hyperaldosteronism) and 55 patients with EH participated. RESULTS: PA patients had higher arterial stiffness than EH patients (P = 0.006), with a lower numbers of circulating EPC and endothelial colony-forming units (P < 0.05). The differences were ameliorated at 6 months after unilateral adrenalectomy or treatment with spironolactone. Expression of MR was identified in the EPC. The number of circulating EPC was inversely correlated with the plasma aldosterone concentration (P = 0.021), arterial stiffness (P = 0.029) and serum high-sensitivity C-reactive protein (P = 0.03). High-dose aldosterone (10(-5) and 10(-6) m) attenuated EPC proliferation and angiogenesis in vitro. Among the 45 patients who underwent unilateral adrenalectomy, 32 (71%) were cured of hypertension. The preoperative number of EPC [log(EPC number percent) >-3.6] predicted the curability of hypertension after adrenalectomy (P = 0.003). CONCLUSIONS: The relative deficiency of EPC in PA patients may contribute to aldosterone vasculopathy, which can be reversed by adrenalectomy and spironolactone. High aldosterone levels attenuated EPC proliferation and angiogenesis. Circulating EPC number may be a valuable biomarker to identify PA patients with a high incidence of arterial stiffness and to predict postoperative residual hypertension of aldosterone-producing adenoma.

Salvianolic acid B inhibits low-density lipoprotein oxidation and neointimal hyperplasia in endothelium-denuded hypercholesterolaemic rabbits.

BACKGROUND: Atherosclerosis and restenosis are inflammatory responses involving free radicals and lipid peroxidation and may be prevented/cured by antioxidant-mediated lipid peroxidation inhibition. Salvianolic acid (Sal B), a water-soluble antioxidant obtained from a Chinese medicinal herb, is believed to have multiple preventive and therapeutic effects against human vascular diseases. In this study the in vitro and in vivo inhibitory effects of Sal B on oxidative stress were determined. RESULTS: In human aortic endothelial cells (HAECs), Sal B reduced oxidative stress, inhibited low-density lipoprotein (LDL) oxidation and reduced oxidised LDL-induced cytotoxicity. Sal B inhibited Cu(2+) -induced LDL oxidation in vitro (with a potency 16.3 times that of probucol) and attenuated HAEC-mediated LDL oxidation as well as reactive oxygen species (ROS) production. In cholesterol-fed New Zealand White rabbits (with probucol as positive control), Sal B intake reduced Cu(2+) -induced LDL oxidation, lipid deposition in the thoracic aorta, intimal thickness of the aortic arch and thoracic aorta and neointimal formation in the abdominal aorta. CONCLUSION: The data obtained in this study suggest that Sal B protects HAECs from oxidative injury-mediated cell death via inhibition of ROS production. The antioxidant activity of Sal B may help explain its efficacy in the treatment of vascular diseases.

Nrf-2 mediated heme oxygenase-1 expression, an antioxidant-independent mechanism, contributes to anti-atherogenesis and vascular protective effects of Ginkgo biloba extract.

AIMS: Vascular protective effects of Ginkgo biloba extract (GBE) may involve both antioxidant-related and anti-inflammatory mechanisms. GBE was recently suggested as a heme oxygenase (HO)-1 inducer. The role of HO-1 in anti-atherogenesis and related vascular protective effects of GBE awaited further clarification. METHODS AND RESULTS: Tumor necrosis factor (TNF)-α was used to stimulate adhesiveness of human aortic endothelial cells (HAECs) to monocytes, an in vitro sign simulating atherogenesis. Pretreatment with GBE reduced TNF-α-stimulated endothelial adhesiveness, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. GBE increased HO-1 expression and enzyme activity in HAECs. Pretreatment with MAP kinase inhibitor SB203580 significantly reduced GBE-induced HO-1 expression. Furthermore, GBE activated the translocation of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increased its binding to the antioxidant response element (ARE) of the HO-1 gene. Pretreatment with PEG-SOD or other antioxidant reagents did not alter GBE-induced endothelial HO-1 expression. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injury arteries, and enhance HO-1 expression in circulating monocytes and in arteries after wire injury, suggesting the in vivo induction of HO-1 by GBE. CONCLUSION: GBE could inhibit cytokine-induced endothelial adhesiveness by inducing HO-1 expression via the activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression.

Atomic layer deposition-based functionalization of materials for medical and environmental health applications.

Nanoporous alumina membranes exhibit high pore densities, well-controlled and uniform pore sizes, as well as straight pores. Owing to these unusual properties, nanoporous alumina membranes are currently being considered for use in implantable sensor membranes and water purification membranes. Atomic layer deposition is a thin-film growth process that may be used to modify the pore size in a nanoporous alumina membrane while retaining a narrow pore distribution. In addition, films deposited by means of atomic layer deposition may impart improved biological functionality to nanoporous alumina membranes. In this study, zinc oxide coatings and platinum coatings were deposited on nanoporous alumina membranes by means of atomic layer deposition. PEGylated nanoporous alumina membranes were prepared by self-assembly of 1-mercaptoundec-11-yl hexa(ethylene glycol) on platinum-coated nanoporous alumina membranes. The pores of the PEGylated nanoporous alumina membranes remained free of fouling after exposure to human platelet-rich plasma; protein adsorption, fibrin networks and platelet aggregation were not observed on the coated membrane surface. Zinc oxide-coated nanoporous alumina membranes demonstrated activity against two waterborne pathogens, Escherichia coli and Staphylococcus aureus. The results of this work indicate that nanoporous alumina membranes may be modified using atomic layer deposition for use in a variety of medical and environmental health applications.

Atorvastatin induces thrombomodulin expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells.

Expression of functionally active thrombomodulin (TM) on endothelial cells is critical for vascular thromboresistance. 3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can protect the vasculature from inflammation and atherosclerosis caused by cholesterol-dependent and cholesterol-independent mechanisms. In the present study, the effects of atorvastatin on TM expression in the aorta of cholesterol-fed rabbits and in TNFalpha-treated human aortic endothelial cells (HAECs) were investigated. When rabbits were fed a 0.5% cholesterol diet with and without supplementation with atorvastatin for 9 weeks, the neointimal area in the thoracic aorta of the atorvastatin-treated group was significantly reduced and there was significant induction of TM protein expression. In HAECs, TNFalpha treatment decreased the expression of TM in a time- and dose-dependent manner and atorvastatin pretreatment upregulated the expression of TM mRNA and protein in HAECs with or without TNFalpha treatment. Atorvastatin also inhibited monocyte adhesion to control and TNFalpha-treated HAECs via TM expression. ERK1/2 phosphorylation was significantly reduced by 24 h pretreatment with atorvastatin, whereas TNFalpha increased the phosphorylation of the MAPKs, p38, JNK, and ERK1/2. Blocking the transcriptional activation of NF-kappaB and nuclear translocation of NF-kappaB p65 prevented the TNFalpha-induced downregulation of TM. Atorvastatin regulated TM expression in control and TNFalpha-treated HAECs by inhibiting the activation of ERK and NF-kappaB. The increase in endothelial TM activity in response to atorvastatin constitutes an important pleiotropic effect of this commonly used compound and may be of clinical significance in cardiovascular disorders in which deficient endothelial TM plays a pathophysiological role.

Anti-inflammatory strategies for homocysteine-related cardiovascular disease.

Homocysteine may induce vascular damage for atherosclerosis. Vitamin/folate supplementation has been proposed to reduce the cardiovascular disease risk. Nevertheless, there is no randomized clinical trial clearly proving the efficacy of reducing the homocysteine as a means of lowering the incidence of cardiovascular disease. Homocysteine induces oxidative stress leading to endothelial dysfunction. In addition, homocysteine-induced oxidative stress favors lipid peroxidation and induces production of inflammatory factors, thus accelerating atherosclerosis. In this paper, we reviewed the available evidence concerning the association between homocysteine and cardiovascular disease, with the objective of discussing the pertinence of screening, treatment, and prevention of hyperhomocysteinemia-related cardiovascular disease. Our previous findings also indicated the significant role of mononuclear cells activation in homocysteine-induced endothelial dysfunction; treatment with statins attenuated homocysteine-induced endothelial adhesiveness, indicating the novel endothelial protection effects of statins in the presence of homocysteine. Since inflammation and oxidative stress are critical to homocysteine-induced vascular damage, the improvement of endothelial dysfunction and the inhibition of mononuclear cell activation by anti-inflammatory and/or antioxidative drugs/agents may serve as the potential therapeutic strategy for hyperhomocysteinemia-related cardiovascular disease.

Nanoporous hard carbon membranes for medical applications.

Current blood glucose sensors have proven to be inadequate for long term in vivo applications; membrane biofouling and inflammation play significant roles in sensor instability. An ideal biosensor membrane material must prevent protein adsorption and promote integration of the sensor with the surrounding tissue. Furthermore, biosensor membranes must be sufficiently thin and porous in order to allow the sensor to rapidly respond to fluctuations in analyte concentration. In this study, the use of diamondlike carbon-coated anodized aluminum oxide as a potential biosensor membrane is discussed. Diamondlike carbon films and diamondlike carbon-coated anodized aluminum oxide nanoporous membranes were examined using scanning electron microscopy, atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and platelet rich plasma testing. The diamondlike carbon-coated anodized aluminum oxide membranes remained free from protein adsorption during in vitro platelet rich plasma testing. We anticipate that this novel membrane could find use in immunoisolation devices, pacemakers, kidney dialysis membranes, microdialysis systems, and other devices facing biocompatibility issues that limit in vivo function.