ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking.

BACKGROUND: Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS: To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS: In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS: RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.

Epidemiology of pediatric multiple sclerosis, neuromyelitis optica, and optic neuritis in Taiwan.

BACKGROUND AND OBJECTIVE: The epidemiology of pediatric acquired demyelinating disorders remains to be clarified in many parts of Asia. We carry out this study to depict the epidemiology of pediatric multiple sclerosis (MS), neuromyelitis optica (NMO), and optic neuritis (ON) in Taiwan. METHODS: We conducted a retrospective nationwide population-based study using data from Taiwan's National Health Insurance Research Database. Prevalent cases of pediatric MS and NMO during 2001-2015, and incident cases of pediatric MS, NMO, and ON during 2003-2015 were identified. The demographic features and comorbidities were investigated. RESULTS: We identified 403 MS, 42 NMO, and 1496 ON incident cases under the age of 20 during 2003-2015. The majority of pediatric MS (86.1%) and NMO (90.5%) patients were 10 years old or above. The incidence of MS and ON was relatively steady, while that of NMO increased prominently later during the study period. The average incidence of pediatric MS and NMO during 2011-2015 was 0.52 and 0.11 per 100,000 person-years, respectively. The female preponderance was evident for pediatric MS and NMO, and less so for pediatric ON. The most common autoimmune comorbidities for pediatric MS were thyrotoxicosis (1.0%) and systemic lupus erythematosus (0.7%). CONCLUSION: The epidemiology of pediatric MS was largely stationary in Taiwan during 2001-2015, while the prevalence of pediatric NMO rose steeply during this period, probably reflecting better recognition of this clinical entity. Autoimmune comorbidities were uncommon for pediatric MS and NMO in Taiwan.

Dipeptidyl Peptidase-4 Inhibitor Use Is Not Associated With Acute Pancreatitis in High-Risk Type 2 Diabetic Patients: A Nationwide Cohort Study.

To analyze the association between use of DPP-4 inhibitors and acute pancreatitis in high-risk type 2 diabetic patients. A retrospective nationwide cohort study was conducted using the Taiwan National Health Insurance claim database. The risk associated with sitagliptin was compared to that with acarbose, a second-line antidiabetic drug prescribed for patients with similar diabetes severity and with a known neutral effect on pancreatitis. Between January 1, 2009 and December 31, 2010, a total of 8526 sitagliptin initiators and 8055 acarbose initiators who had hypertriglyceridemia or prior hospitalization history for acute pancreatitis were analyzed for the risk of hospitalization due to acute pancreatitis stratified for baseline propensity score. In the crude analysis, sitagliptin was associated with a decreased risk of acute pancreatitis (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.62-0.88) compared to acarbose in diabetic patients with prior history of hospitalization for pancreatitis or hypertriglyceridemia. The association was abolished after stratification for propensity score quintiles (adjusted HR 0.95; 95% CI: 0.79-1.16). Similar results were found separately in both patients' histories of prior hospitalization of acute pancreatitis (adjusted HR 0.97; 95% CI: 0.76-1.24) and those with hypertriglyceridemia (adjusted HR 0.86; 95% CI: 0.65-1.13). No significant association was found for different durations or accumulative doses of sitagliptin. In the stratified analysis, no significant effect modification was found in relation to patients' characteristics. Use of sitagliptin was not associated with an increased risk of acute pancreatitis in high-risk diabetic patients with hypertriglyceridemia or with history of acute pancreatitis.

Time trends in the prevalence and incidence of Parkinson's disease in Taiwan: A nationwide, population-based study.

BACKGROUND/PURPOSE: Identifying trends in the prevalence and incidence of Parkinson's disease (PD) may yield information that supports public health goals. Our aim was to evaluate time-trend changes in the prevalence and incidence of PD in Taiwan between 2004 and 2011. METHODS: This retrospective, nationwide, longitudinal study used the Taiwan National Health Insurance Research Database to identify patients with PD from 2004 to 2011 based on having ICD-9-CM diagnostic codes, which were assigned by neurologists, and being prescribed PD medication. Annual incidence and prevalence were calculated, and time-trend analyses were estimated assuming a Poisson distribution. RESULTS: Over the study period, 19,302 patients in 2004 and 41,606 patients in 2011 fulfilling the study criteria for PD were included in the analysis. The average age-standardized prevalence of PD per 100,000 of population was 84.8 in 2004 and 147.7 in 2011, with a 7.9% yearly increase. Increasing prevalence trends of PD were statistically significant (p < 0.001) in all age groups, with the steepest rate among those aged ≥ 80 years. In contrast, the average age-standardized incidence of PD decreased steadily from 35.3 per 100,000 in 2005 to 28.8 per 100,000 in 2011. The incidence rate was higher in men than in women, and increased with age. CONCLUSION: We identified an increasing trend in the annual prevalence rates of PD from 2004 to 2011; however, the substantial decline in the incidence of PD suggests that some major environmental risk factors for PD were removed from this population during this time period.

Cardiovascular risk associated with acarbose versus metformin as the first-line treatment in patients with type 2 diabetes: a nationwide cohort study.

CONTEXT: Metformin is the first-line oral therapy for type 2 diabetes with proven benefits against cardiovascular risk. Recent evidence suggested that acarbose might be similar to metformin in glucose-lowering efficacy and cardiovascular risk reduction. Therefore, international guidelines have suggested the use of acarbose as alternative first-line antidiabetic therapy. OBJECTIVE: To compare the cardiovascular outcomes in the first-line users of acarbose vs metformin. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: A nationwide cohort study was conducted by analyzing the Taiwan National Health Insurance (NHI) Database. A total of 17,366 acarbose initiators and 230,023 metformin initiators were identified between January 1, 2009 and December 31, 2010. The primary outcome is hospitalization due to any cardiovascular events, including acute myocardial infarction, congestive heart failure, and ischemic stroke. The propensity score method was used to adjust for baseline differences between the two groups. Patients were followed from drug initiation to the earliest of outcome occurrence, death or disenrollment from NHI, or study termination. RESULTS: In intention-to-treat analyses, acarbose was associated with a higher risk of any cardiovascular event (adjusted hazard ratio [HR]: 1.05; 95% confidence interval [CI], 1.01-1.09), heart failure (HR, 1.08; 95% CI, 1.00-1.16), and ischemic stroke (HR, 1.05, 95% CI, 1.00-1.10) than metformin. No significant difference in risk was found in subgroups of patients with or without underlying hypertension, ischemic heart disease, or cerebrovascular disease. Similar results were found in auxiliary as-treated analyses or analyses stratified by propensity score quintiles. CONCLUSION: Our data do not support that acarbose has a cardio-protective effect similar to metformin as a first-line antidiabetic agent.

Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study.

BACKGROUND AND AIM: The hepatotoxicity of statins in patients with chronic liver diseases remains unclear. In this study, we aimed to estimate the risk of severe hepatic injury associated with different statins in patients with chronic liver disease. METHODS: A nationwide population-based cohort study was conducted by analyzing the Taiwan National Health Insurance database. A total of 37,929 subjects with chronic liver disease who started statin therapy were identified during the period of January 1, 2005 to December 31, 2009. Outcome was defined as hospitalization due to liver injury. RESULTS: During a total of 118,772 person-years of follow-up, 912 incident cases of hospitalization due to hepatic injury are identified. The incidence rate was 2.95, 2.49, 2.92, 1.94, 2.65, and 2.52 per 100,000 person-days for atorvastatin, lovastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin initiators, respectively. Overall, there was no difference in the incidence associated with different statins. However, when each statin was further categorized to high (≧ 0.5 defined daily dose) or low (< 0.5 defined daily dose) mean daily dose, only high-dose atorvastatin was significantly associated with increased risk of hospitalization due to hepatic injury (hazard ratio, 1.62; 95% confidence interval, 1.29, 2.03) as compared with low-dose atorvastatin. CONCLUSION: The overall incidence of hospitalization due to severe hepatic injury was low among statin initiators with chronic liver disease. Only high-dose atorvastatin was associated with increased risk.

Effectiveness and safety of extracranial carotid stent placement: a nationwide self-controlled case-series study.

BACKGROUND: Carotid angioplasty and stent (CAS) placement has emerged as an attractive revascularization strategy for patients with internal carotid artery stenosis. However, the effectiveness and safety of CAS were not fully evaluated, mainly because of methodological difficulties in finding an appropriate comparison group. METHODS: Patients who underwent CAS were identified from Taiwan's National Health Insurance claims database between 2005 and 2008. The incidence rate of ischemic stroke after CAS was compared with that of the year prior to the procedure using a self-controlled case series analysis and a conditional Poisson regression model. Logistic regression was conducted to identify factors associated with poor outcome. RESULTS: A total of 1258 patients who had undergone CAS were included, and 73 cases (5.8%) of death or ischemic stroke occurred during the index hospitalization. Within 1 year after CAS, 74 patients died and 80 experienced an ischemic stroke. Of the 1184 patients who were followed for 360 days, the rate ratio for ischemic stroke decreased to 0.21 (95% CI: 0.08-0.51) between 31 and 180 days, and 0.10 (95% CI: 0.03-0.32) between 181 and 360 days. Statin therapy was associated with a reduced risk of death or ischemic stroke in the 1(st) month (odds ratio of 0.53; 95% CI: 0.32-0.90). Conversely, the use of nonsteroidal anti-inflammatory agents, possibly histamine-2 receptor blockers, and CAS performed by low-volume operators were associated with a twofold increased risk. CONCLUSION: CAS reduced the long-term risk for ischemic stroke. Self-controlled case series analysis might be an appropriate design for evaluating device safety and effectiveness.

Risk of Parkinson's disease following severe constipation: a nationwide population-based cohort study.

INTRODUCTION: Constipation is a non-motor symptom of Parkinson's disease (PD). We investigated the association between the severity of constipation and subsequent risk of PD in a population-based sample. METHODS: 551,324 participants free of PD, dementia, and stroke were retrospectively ascertained between January 1, 2005 and December 31, 2005 using the Taiwan National Health Insurance Research Database. The association between constipation at the beginning of the study and the incidence of PD was examined using a Cox regression model. Information regarding comorbidities and concomitant medications use was adjusted in the proportional hazards models. RESULTS: After an average follow-up of 5.5 years, 2336 incident PD cases were diagnosed. The crude incidence rate of PD per 1,000,000 person-days was 1.57 for subjects without constipation and 4.04, 5.28, and 12.67 for mild, moderate, and severe constipation, respectively. After adjusting for age, sex, comorbidities, and concomitant medication use, patients with constipation were more likely to develop PD than subjects without constipation; the adjusted hazard ratio (aHR) was 3.28 (95% CI: 2.14-5.03), 3.83 (2.51-5.84), and 4.22 (2.95-6.05) for individual constipation severity categories. Constipation severity was also associated with an increased likelihood of PD in the time-varying analysis; the aHR was 2.84 (2.43-3.33), 5.22 (4.61-5.92), and 10.47 (9.46-11.58) for mild, moderate, and severe constipation, respectively (P < 0.0001). After excluding PD patients diagnosed within 3 years of constipation, the association remained significant. CONCLUSIONS: Our study suggests that the severity of constipation is associated with a future diagnosis of PD in a dose-dependent manner.

Mercury exposure and omega-3 fatty acid intake in relation to renal function in the US population.

It remains unclear whether exposure to low-level mercury (Hg) is associated with impaired renal function, and whether omega-3 fatty acid (FA) intake could affect the association of interest. The current study examined the association of blood Hg and omega-3 FAs with renal function using data from 1046 subjects aged 40 or above from the 2003-2004 National Health and Nutrition Examination Survey. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and occurrence of albuminuria. Logistic regression analyses were applied to assess the association of interest with confounding variable adjustment. The analyses indicated that blood Hg was associated with reduced eGFR (<60mL/min/1.73m(2)) in a dose-response fashion (p<0.05). The association was particularly apparent with adjustment for blood omega-3 FA levels. The adjusted odds ratio for having reduced eGFR was 2.94 (95% confidence interval=1.04-8.33) in the highest tertile of blood Hg as compared with the lowest tertile. There was no significant association between Hg exposure and albuminuria. In summary, this study demonstrates that Hg exposure is associated with increased odds of having lower GFR in the US population aged 40 or above. A statistical association with albuminuria was not apparent. We also observed that omega-3 FA intake may play a preventive role in Hg-induced nephrotoxicity. Additional studies are warranted to determine the sources, exposure routes, and forms of Hg most responsible for observed associations.

Cigarette smoking, cadmium exposure, and zinc intake on obstructive lung disorder.

BACKGROUND AND OBJECTIVE: This study examined whether zinc intake was associated with lower risk of smoking-induced obstructive lung disorder through interplay with cadmium, one of major toxicants in cigarette smoke. METHODS: Data were obtained from a sample of 6,726 subjects aged 40+ from the Third National Health and Nutrition Examination Survey. The forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using spirometry. Gender-, ethnicity-, and age-specific equations were used to calculate the lower limit of normal (LLN) to define obstructive lung disorder as: observed FEV1/FVC ratio and FEV1 below respective LLN. Zinc intake was assessed by questionnaire. Logistic regression analysis was applied to investigate the associations of interest. RESULTS: The analyses showed that an increased prevalence of obstructive lung disorder was observed among individuals with low zinc intake regardless of smoking status. The adjusted odds of lung disorder are approximately 1.9 times greater for subjects in the lowest zinc-intake tertile than those in the highest tertile (odds ratio = 1.89, 95% confidence interval = 1.22-2.93). The effect of smoking on lung function decreased considerably after adjusting for urinary cadmium. Protective association between the zinc-to-cadmium ratio (log-transformed) and respiratory risk suggests that zinc may play a role in smoking-associated lung disorder by modifying the influence of cadmium. CONCLUSIONS: While zinc intake is associated with lower risk of obstructive lung disorder, the role of smoking cession and/or prevention are likely to be more important given their far greater effect on respiratory risk. Future research is warranted to explore the mechanisms by which zinc could modify smoking-associated lung disease.