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.

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.

Using CRISPR/Cas9-Mediated GLA Gene Knockout as an In Vitro Drug Screening Model for Fabry Disease.

The CRISPR/Cas9 Genome-editing system has revealed promising potential for generating gene mutation, deletion, and correction in human cells. Application of this powerful tool in Fabry disease (FD), however, still needs to be explored. Enzyme replacement therapy (ERT), a regular administration of recombinant human α Gal A (rhα-GLA), is a currently available and effective treatment to clear the accumulated Gb3 in FD patients. However, the short half-life of rhα-GLA in human body limits its application. Moreover, lack of an appropriate in vitro disease model restricted the high-throughput screening of drugs for improving ERT efficacy. Therefore, it is worth establishing a large-expanded in vitro FD model for screening potential candidates, which can enhance and prolong ERT potency. Using CRISPR/Cas9-mediated gene knockout of GLA in HEK-293T cells, we generated GLA-null cells to investigate rhα-GLA cellular pharmacokinetics. The half-life of administrated rhα-GLA was around 24 h in GLA-null cells; co-administration of proteasome inhibitor MG132 and rhα-GLA significantly restored the GLA enzyme activity by two-fold compared with rhα-GLA alone. Furthermore, co-treatment of rhα-GLA/MG132 in patient-derived fibroblasts increased Gb3 clearance by 30%, compared with rhα-GLA treatment alone. Collectively, the CRISPR/Cas9-mediated GLA-knockout HEK-293T cells provide an in vitro FD model for evaluating the intracellular pharmacokinetics of the rhα-GLA as well as for screening candidates to prolong rhα-GLA potency. Using this model, we demonstrated that MG132 prolongs rhα-GLA half-life and enhanced Gb3 clearance, shedding light on the direction of enhancing ERT efficacy in FD treatment.

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.

Age-Related Macular Degeneration and Risk of Degenerative Dementia among the Elderly in Taiwan: A Population-Based Cohort Study.

PURPOSE: To investigate the relationship between age-related macular degeneration (AMD) and future development of Alzheimer's disease (AD) or senile dementia. DESIGN: A longitudinal case-control study using the Taiwan National Health Insurance Research Database. PARTICIPANTS: From 2001 to 2009, the newly diagnosed AMD cases aged ≥65 years in the database were recruited as the AMD cohort (n=4993). Of those, there were 540 with and 4453 without exudative AMD diagnoses. Subjects without any AMD, matched for age, gender, and time of enrollment, were randomly sampled as the control cohort (n=24,965) for comparison. METHODS: Alzheimer's disease/senile dementia-free survival analysis was assessed using a Kaplan-Meier method. Cox proportional hazard regressions were performed to calculate the hazard ratios (HR) of AD or senile dementia for the 2 cohorts after adjusting for preexisting comorbidities and number of clinical visits. MAIN OUTCOME MEASURES: The first-ever diagnosis of AD or senile dementia during the observation period. RESULTS: Of the 29 958 sampled subjects, 1589 (5.3%) were diagnosed with AD or senile dementia during a mean follow-up period of 4.4 years, including 294 (5.9%) from the AMD cohort and 1295 (5.2%) from the control cohort. The incidence of AD or senile dementia was higher in patients with AMD than in the controls (P=0.044), with an HR of 1.44 (95% confidence interval [CI], 1.26-1.64) after adjusting for covariates. The stratified analysis showed that the adjusted HR for AD or senile dementia was 1.35 (95% CI, 0.89-2.06) for exudative AMD versus the controls and 1.44 (95% CI, 1.26-1.65) for nonexudative AMD versus the controls. CONCLUSIONS: This study provides large-scale, population-based evidence that AMD, especially nonexudative AMD, is independently associated with an increased risk of subsequent AD or senile dementia development.

Mammography and the risk of thyroid and hematological cancers: a nationwide population-based study.

To investigate the association between thyroid cancer as well as the most radiosensitive hematological cancers and radiation exposure from mammography. This study used information from a random sample of two million persons enrolled in the nationally representative Taiwan National Health Insurance (NHI) Research Database. The exposed group was composed of women aged 18-65 who had undergone diagnostic mammography between 2000 and 2007. The nonexposed control group was composed of women in the NHI database who had never undergone diagnostic mammography. There were 25,362 women in the exposed group and 203,317 women in the nonexposed group. After adjusting for age and comorbidities, the patients who had been exposed to radiation from mammography did not have a significantly higher risk of developing thyroid cancer and hematological cancers (adjusted HR, 1.201; 95% CI, 0.813-1.774 for thyroid cancer and adjusted HR, 1.228; 95% CI, 0.838-1.800 for hematological cancers). The scattered radiation dose delivered by mammography should be cautiously handled, but no additional concerns about the risk of thyroid cancer developing malignancy should be emphasized.

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.

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.

Sleep apnea and risk of retinal vein occlusion: a nationwide population-based study of Taiwanese.

PURPOSE: To explore the relationship of sleep apnea and the subsequent development of retinal vein occlusion (RVO). DESIGN: A retrospective nonrandomized, matched-control cohort study using the Taiwan National Health Insurance Research Database. METHODS: From 1997 through 2007, we identified newly diagnosed sleep apnea cases in the database. A control group without sleep apnea, matched for age, gender, and comorbidities, was selected for comparison. The 2 cohorts were followed up, and the occurrence of RVO was observed. RESULTS: Of the 35 634 sampled patients (5965 sleep apnea patients vs 29 669 controls), 52 (0.15%) experienced RVO during a mean follow-up period of 3.72 years, including 13 (0.22%, all branch RVO) from the sleep apnea cohort and 39 (0.13%, 39 branch RVO and 10 central RVO) from the control group. Kaplan-Meier analysis revealed the tendency of sleep apnea patients toward RVO development (P = .048, log-rank test). Patients with sleep apnea experienced a 1.94-fold increase (95% confidence interval, 1.03 to 3.65; P = .041) in incident RVO, which was independent of age, gender, and comorbidities. CONCLUSIONS: Sleep apnea may be an independent risk factor for RVO.

Monascus purpureus-fermented rice inhibits tumor necrosis factor-α-induced upregulation of matrix metalloproteinase 2 and 9 in human aortic smooth muscle cells.

OBJECTIVES: Inflammation is associated with atherosclerosis. Cholestin (Monascus purpureus-fermented rice) contains a naturally occurring statin, which has lipid-modulating, anti-inflammatory and antioxidative effects. This study aimed to investigate the effects of Cholestin extract on the expression of matrix metalloproteinase (MMP)-2 and MMP-9 by tumor necrosis factor (TNF)-α-treated human aortic smooth muscle cells (HASMCs). METHODS: Zymography, reverse transcription polymerase chain reaction and immunoblot analyses were used for analysis of MMP expression of TNF-α-stimulated HASMCs. Gel shift assay was used for analysis of transcription factor nuclear factor-κB (NF-κB) activation. Intracellular reactive oxygen species (ROS) generation was also analysed. KEY FINDINGS: The supplement of HASMCs with Cholestin extract significantly suppresses enzymatic activities of MMP-2 and MMP-9 in TNF-α-stimulated HASMCs. RT-PCR and immunoblot analyses show that Cholestin extract significantly attenuates TNF-α-induced mRNA and protein expressions of MMP-2 and MMP-9. Gel shift assays show that Cholestin treatment reduces TNF-α-activated NF-κB. Furthermore, Cholestin also attenuates intracellular ROS generation in TNF-α-treated HASMCs. The supplement with an ROS scavenger N-acetyl-cysteine (glutathione precursor) gives similar results to Cholestin. CONCLUSIONS: Cholestin reduces TNF-α-stimulated MMP-2 and MMP-9 expression as well as downregulating NF-κB activation and intracellular ROS formation in HASMCs, supporting the notion that the natural compound Cholestin may have potential application in clinical atherosclerosis disease.

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.

Exposure to sennoside-digoxin interaction and risk of digoxin toxicity: a population-based nested case-control study.

AIMS: Digoxin is an important medication for heart failure (HF) patients and sennosides are widely used to treat constipation. Recently, safety concerns have been raised about a possible interaction between sennosides and digoxin, an issue that has not been studied empirically. This study therefore aimed to evaluate whether exposure to sennoside-digoxin interaction is associated with an increased risk of digoxin toxicity. METHODS AND RESULTS: This was a population-based nested case-control study that analysed data obtained from the Taiwan National Health Insurance Research Database between 1 January 2001 and 31 December 2004. All HF patients treated with digoxin for the first time were included as the study cohort. Of these, cases were identified as subjects hospitalized for digoxin toxicity (International Classification of Diseases, Ninth Revision, Clinical Modification, ICD-9-CM 972.1), and matched to randomly selected controls. Use of sennosides was compared between the two groups. Odds ratios (ORs) were employed to quantify the risk associated with exposure to sennoside-digoxin interaction by conditional logistic regression. The study cohort comprised 222,527 HF patients, of whom 524 were identified as cases and 2,502 as matched controls. Use of sennosides during the 14 days preceding the index date was found to be associated with a 1.61-fold increased risk of digoxin toxicity [95% confidence interval (CI) = 1.15, 2.25]. Additionally, a greater risk was observed for sennosides prescribed at an average daily dose ≥ 24 mg (adjusted OR = 1.93; 95% CI = 1.27, 2.94). CONCLUSION: The combined use of sennosides and digoxin was found to be associated with a modest increased risk of digoxin toxicity in HF patients.

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.