Low serum phosphate is associated with ischemic stroke in hemodialysis patients.

BACKGROUND: Hemodialysis patients have a high incidence of ischemic stroke. However, the association between serum phosphate levels and ischemic stroke is controversial among hemodialysis patients. The present study is used to evaluate whether serum phosphate levels are associated with ischemic stroke among patients undergoing hemodialysis. METHODS: A total of 84 hemodialysis patients were followed up for 8 years. Data collection included chart reviews and assessments of laboratory records. The ischemic stroke diagnosis was made on the basis of history, physical examination and neuroimaging (computed tomography and/or magnetic resonance imaging) by neurologists. Cox proportional hazard regression models were used to analyze the data. RESULTS: During the follow-up period, 29 patients experienced ischemic stroke. According to Cox proportional hazard regression analysis, the risk of ischemic stroke decreased by 45.5% for each 1-mg/dL increase in averaged serum phosphate (HR 0.545, p = 0.011). The risk of ischemic stroke increased by 4.3% for each 1-year increase in age (HR 1.043, p = 0.018). The risk of ischemic stroke increased by 1.1% increase for each 103/µL increase in averaged blood platelet (HR 1.011, p = 0.009). The risk of ischemic stroke in patients with averaged serum phosphate < 4.5 mg/dL increased 3.40-fold more than patients with averaged serum phosphate ≥ 4.5 mg/dL (HR 3.400, p = 0.025). CONCLUSIONS: Low serum phosphate is a risk factor for developing ischemic stroke in hemodialysis patients. The results suggest that managing serum phosphate ≥ 4.5 mg/dL among hemodialysis patients may reduce the risk of ischemic stroke.

Association of migraines with brain tumors: a nationwide population-based study.

BACKGROUND: Several studies examined headaches as a symptom of brain neoplasms. Nevertheless, very few studies attempted to specifically evaluate the role of headaches as a risk factor. This study aimed to investigate the risk of migraine occurrence in the preceding years among patients diagnosed with brain tumors and unaffected controls. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. In total, 11,325 adults with a first-time brain tumor diagnosis were included as cases, together with 11,325 unaffected matched controls. Each individual was traced in the healthcare claims dataset for a prior diagnosis of migraines. Conditional logistic regressions were performed to calculate the odds ratio (OR) and the corresponding 95% confidence interval (CI) to present the association between brain tumors and having previously been diagnosed with migraines. RESULTS: We found that among patients with and those without brain tumors, 554 (4.89%) and 235 (2.08%) individuals, respectively, were identified as having a prior migraine diagnosis. Compared to unaffected controls, patients with brain tumors experienced an independent 2.45-fold increased risk of having a prior migraine diagnosis. The risks were even higher among men (odds ratio (OR) = 3.04, 95% confidence interval (CI) = 2.29~ 4.04) and after patients who had received a prior migraine diagnosis within 3 years were excluded (OR = 1.91, 95% CI = 1.59~ 2.29). CONCLUSIONS: This is the first report demonstrating the occurrence of brain tumors to be associated with a prior migraine history, for both men and women, in a population-based study.

Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved.

Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. "Stimulated by retinoic acid 6" (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFß1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1(-/-) mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease.

A population-based study on the associations between chronic periodontitis and the risk of cancer.

BACKGROUND: To date, the associations between chronic periodontitis (CP) and cancer lack large-scale population-based epidemiological evidence. This study aimed to investigate the subsequent risk for cancers among subjects with CP. METHODS: This study cohort included 40,140 subjects with CP and 40,140 subjects who were matched for a comparison cohort. We individually tracked each patient for a 5-year period following their index date to identify those who had received a diagnosis of cancer. RESULTS: The incidence rate of cancer during the 5-year follow-up period was 14.80 (95 % CI 14.28-15.34) per 1,000 person-years in subjects with CP. Cox proportional hazards regression revealed that the hazard ratio of cancer during the 5-year follow-up period for subjects with CP was 1.23 (95 % CI 1.20-1.27) compared to that of the comparison cohort. CONCLUSION: We observed an increased risk for the subsequent development of a number of cancers among subjects with CP.

Appendectomy increased the risk of ischemic heart disease.

BACKGROUND: Although the appendix may not be considered vital, recent studies have noted adverse health consequences after appendectomy. This study aimed to use a population-based data set to explore whether appendectomy increases the risk for subsequent ischemic heart disease (IHD) in a 3-y follow-up period. MATERIALS AND METHODS: This study used data from the Longitudinal Health Insurance Database 2000 in Taiwan. The study cohort included 5413 patients who underwent appendectomies. The comparison cohort was selected by randomly recruiting 16,239 enrollees matched with the study group in terms of sex, age, hypertension, hyperlipidemia, and diabetes. Each individual was tracked for 3 y to identify whether he and/or she developed IHD during the follow-up period. Cox proportional hazard regressions were performed for analysis. RESULTS: During a 3-y follow-up, 196 (3.62%) and 375 (2.31%) IHD incidents developed in the study and the comparison cohorts, respectively. For adults aged ≥18 y, experiencing an appendectomy was independently associated with a 1.54-fold increased risk of IHD during the 3 y of follow-up (95% CI = 1.29-1.84). The association persisted in further analyses stratified by age. CONCLUSIONS: There is an increased risk of subsequent IHD within 3 y after appendectomy, and this underscores the need for more serious clinical decision-making in removing the appendix. Regular monitoring for IHDs is also recommended for patients who have undergone an appendectomy.

Association of Peripheral Vestibular Disorder with Diabetes: A Population-Based Study.

BACKGROUND: This study aimed to investigate the association of peripheral vestibular disorders with type 1 and type 2 diabetes using a population-based dataset. METHODS: The data for this study were obtained from Taiwan's Longitudinal Health Insurance Database 2010. The sample consisted of 150,916 patients who were newly diagnosed with peripheral vestibular disorders as cases and 452,748 propensity-score-matching controls without peripheral vestibular disorders. We utilized multivariate logistic regression models to quantitatively evaluate the association between peripheral vestibular disorders and diabetes while considering factors such as sex, age, geographic location, monthly income, urbanization level of the patient's residence, coronary heart disease, hypertension, and hyperlipidemia. RESULTS: The chi-squared test indicates that diabetes was more common in the peripheral vestibular disorder group compared to controls (20.6% vs. 15.1%, p < 0.001). Of all sampled patients, the adjusted odds ratio for diabetes was 1.597 (95% CI = 1.570~1.623) for those with peripheral vestibular disorders when compared to controls, while patients with Ménière's disease, benign paroxysmal positional vertigo, unilateral vestibulopathy, and other peripheral vestibular disorders had respective adjusted odds ratios of diabetes at 1.566 (95% CI = 1.498~1.638), 1.677 (95% CI = 1.603~1.755), 1.592 (95% CI = 1.504~1.685), and 1.588 (95% CI = l.555~1.621) in comparison to controls. CONCLUSIONS: Our research has revealed an association between diabetes and an increased susceptibility to peripheral vestibular disorders.

Development of antibody-detection ELISA based on beta-bungarotoxin for evaluation of the neutralization potency of equine plasma against Bungarus multicinctus in Taiwan.

Animal testing has been the primary approach to assess the neutralization potency of antivenom for decades. However, the necessity to sacrifice large numbers of experimental animals during this process has recently raised substantial welfare concerns. Furthermore, the laborious and expensive nature of animal testing highlights the critical need to develop alternative in vitro assays. Here, we developed an antibody-detection enzyme-linked immunosorbent assay (ELISA) technique as an alternative approach to evaluate the neutralization potency of hyperimmunized equine plasma against B. multicinctus, a medically important venomous snake in Taiwan. Firstly, five major protein components of B. multicinctus venom, specifically, α-BTX, ß-BTX, γ-BTX, MTX, and NTL, were isolated. To rank their relative medical significance, a toxicity score system was utilized. Among the proteins tested, ß-BTX presenting the highest score was regarded as the major toxic component. Subsequently, antibody-detection ELISA was established based on the five major proteins and used to evaluate 55 hyperimmunized equine plasma samples with known neutralization potency. ELISA based on ß-BTX, the most lethal protein according to the toxicity score, exhibited the best sensitivity (75.6 %) and specificity (100 %) in discriminating between high-potency and low-potency plasma, supporting the hypothesis that highly toxic proteins offer better discriminatory power for potency evaluation. Additionally, a phospholipase A2 (PLA2) competition process was implemented to eliminate the antibodies targeting toxicologically irrelevant domains. This optimization greatly enhanced the performance of our assay, resulting in sensitivity of 97.6 % and specificity of 92.9 %. The newly developed antibody-detection ELISA presents a promising alternative to in vivo assays to determine the neutralization potency of antisera against B. multicinctus during the process of antivenom production.

Increased unbound retinol-binding protein 4 concentration induces apoptosis through receptor-mediated signaling.

The increase of apo-/holo-retinol-binding protein 4 (RBP4) concentrations has been found in subjects with renal dysfunction and even in diabetic patients with microalbuminuria. Holo-RBP4 is recognized to possess cytoprotective function. Therefore, we supposed that the relative increase in apo-RBP4 might induce cell damage. In this study, we investigated the signal transduction that activated apoptosis in response to the increase of apo-/holo-RBP4 concentration. We found that increase of apo-/holo-RBP4 concentration ratio delayed the displacement of RBP4 with "stimulated by retinoic acid 6" (STRA6), enhanced Janus kinase 2 (JAK2)/STAT5 cascade, up-regulated adenylate cyclase 6 (AC6), increased cAMP, enhanced JNK1/p38 cascade, suppressed CRBP-I/RARα (cellular retinol-binding protein/retinoic acid receptor α) expression, and led to apoptosis in HK-2 and human umbilical vein endothelial cells. Furthermore, STRA6, JAK2, STAT5, JNK1, or p38 siRNA and cAMP-PKA inhibitor reversed the repression of CRBP-I/RARα and apoptosis in apo-RBP4 stimulation. In conclusion, this study indicates that the increase of apo-/holo-RBP4 concentration may influence STRA6 signaling, finally causing apoptosis.

Roles of biochemistry data, lifestyle, and inflammation in identifying abnormal renal function in old Chinese.

BACKGROUND: The incidence of chronic kidney disease (CKD) has dramatically increased in recent years, with significant impacts on patient mortality rates. Previous studies have identified multiple risk factors for CKD, but they mostly relied on the use of traditional statistical methods such as logistic regression and only focused on a few risk factors. AIM: To determine factors that can be used to identify subjects with a low estimated glomerular filtration rate (L-eGFR < 60 mL/min per 1.73 m2) in a cohort of 1236 Chinese people aged over 65. METHODS: Twenty risk factors were divided into three models. Model 1 consisted of demographic and biochemistry data. Model 2 added lifestyle data to Model 1, and Model 3 added inflammatory markers to Model 2. Five machine learning methods were used: Multivariate adaptive regression splines, eXtreme Gradient Boosting, stochastic gradient boosting, Light Gradient Boosting Machine, and Categorical Features + Gradient Boosting. Evaluation criteria included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), F-1 score, and balanced accuracy. RESULTS: A trend of increasing AUC of each was observed from Model 1 to Model 3 and reached statistical significance. Model 3 selected uric acid as the most important risk factor, followed by age, hemoglobin (Hb), body mass index (BMI), sport hours, and systolic blood pressure (SBP). CONCLUSION: Among all the risk factors including demographic, biochemistry, and lifestyle risk factors, along with inflammation markers, UA is the most important risk factor to identify L-eGFR, followed by age, Hb, BMI, sport hours, and SBP in a cohort of elderly Chinese people.

Poloxamer-188 Adjuvant Efficiently Maintains Adaptive Immunity of SARS-CoV-2 RBD Subunit Vaccination through Repressing p38MAPK Signaling.

Poloxamer-188 (P188) is a nonionic triblock linear copolymer that can be used as a pharmaceutical excipient because of its amphiphilic nature. This study investigated whether P188 can act as an adjuvant to improve the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor binding domain (RBD) subunit vaccine. BALB/c mice were vaccinated twice with the RBD antigen alone or in combination with P188 or MF59 (a commercial adjuvant for comparison purposes). The resulting humoral and cellular immunity were assessed. Results showed that P188 helped elicit higher neutralizing activity than MF59 after vaccination. P188 induced significant humoral immune response, along with type 1 T helper (Th1) and type 2 T helper (Th2) cellular immune response when compared with MF59 due to repressing p38MAPK phosphorylation. Furthermore, P188 did not result in adverse effects such as fibrosis of liver or kidney after vaccination. In conclusion, P188 is a novel adjuvant that may be used for safe and effective immune enhancement of the SARS-CoV-2 RBD antigen.

Therapeutic DNA vaccine encoding CEMIP (KIAA1199) ameliorates kidney fibrosis in obesity through inhibiting the Wnt/ß-catenin pathway.

BACKGROUND: CEMIP is a novel risk factor of various cancers through activating Wnt/ß-catenin /epithelial-mesenchymal transition between epithelial cells and stroma. The chronic fibrosis commonly contributes renal carcinogenesis in patients with obesity. As there have very few choices of medicines targeting CEMIP. This study intended to design therapeutic DNA vaccines for nephropathy in obesity, through diminishing the CEMIP/Wnt1/ß-catenin pathway. METHOD: In an 8-week experiment, plasmid-encoding CEMIP was vaccinated into high-fat diet (HFD) or obesity mice in the first 4 weeks, and then vaccination was stopped for at least 4 weeks. Then, plasma and spleens were harvested to evaluate anti-CEMIP antibody synthesis and T-helper type 1 and 2 activation after vaccination. Kidneys were collected to investigate efficacy of CEMIP DNA vaccine on inhibiting HFD and obesity-induced fibrosis and Wnt1/ß-catenin pathway. To confirm that CEMIP crucially contributed towards fibrotic formation, CEMIP gene or siRNA transfection was performed in HK-2 cells under VLDL stimulation, or not. RESULTS: At the end point, anti-CEMIP antibody was successfully produced in the pcDNA 3.1-CEMIP vaccinated group, while Wnt1/ß-catenin signaling and fibrosis was inactive. Through VLDL stimulation and CEMIP overexpression, Wnt1/ß-catenin signaling and fibrosis significantly presented in vitro. Otherwise, anti-sera of CEMIP-vaccinated mice could inhibit the VLDL-induced Wnt1/ß-catenin/fibrosis pathway in HK-2 cells. Similarly, the silencing of CEMIP by siRNA ameliorated the Wnt1/ß-catenin pathway and fibrogenesis under VLDL stimulation. CONCLUSION: DNA vaccine targeting CEMIP/Wnt1/ß-catenin pathway plays a novel strategy in nephropathy. GENERAL SIGNIFICANCE: Immune therapy might provide a new therapeutic option on nephropathy of obesity.

Association of increasing surgeon age with decreasing in-hospital mortality after coronary artery bypass graft surgery.

BACKGROUND: The aim of this study was to investigate the relation between surgeon age and in-hospital mortality for patients who underwent a coronary artery bypass graft (CABG) using a nationwide population-based data set. METHODS: This study used data from the 2004 Taiwan National Health Insurance Research Database. The study sample comprised 3766 patients hospitalized for CABG surgery and was divided into three equal-sized surgeon age groups: <40, 40 to 45, and >45 years. A conditional (fixed-effect) logistic regression was performed to examine the relation between surgeon age and in-hospital mortality after adjusting for surgeon CABG caseload and characteristics of patients and surgeons as well as the clustering effect among surgeons. RESULTS: Patients who underwent CABG performed by surgeons in the <40 years age group had significantly higher in-hospital mortality rates (5.4%) than those operated on by surgeons in the 40- to 45-year age group (3.5%) and surgeons in the >45-year age group (2.6%). Regression shows that the adjusted odds ratio of in-hospital mortality for patients operated on by surgeons in the <40-year age group was 1.47 (p < 0.05) times that for surgeons in the 40- to 45-year age group and 1.82 (p < 0.05) times that for surgeons in the >45-year age group. CONCLUSION: We conclude that older surgeons are more likely to achieve better clinical performance with CABG surgery because of their greater clinical experience.

Seasonal variation in the incidence of spontaneous pneumothorax and its association with climate: a nationwide population-based study.

UNLABELLED: This study investigated seasonal variation in the incidence of spontaneous pneumothorax (SP) among young adults aged 15-44 years, in order to identify possible associations with meteorological parameters in a subtropical Asian climate. Neither particular months nor seasons of the year were significantly associated with the incidence of SP. BACKGROUND AND OBJECTIVE: While links between meteorological conditions and the incidence of spontaneous pneumothorax (SP) have been postulated, the findings are controversial. In this first large-scale, nationwide, population-based study, seasonal variation in the incidence of SP among young adults aged 15-44 years was investigated, in order to identify possible associations with meteorological parameters (rainfall, ambient temperature, relative humidity, atmospheric pressure, hours of sunshine) in a subtropical Asian climate. METHODS: Data (2001-2005) from the National Health Insurance Research Database were used to identify a total of 8575 patients who had been hospitalized with a principal diagnosis of SP. The autoregressive integrated moving average method was used to evaluate the effects of seasonality and monthly climatic factors on the incidence of SP. RESULTS: The incidence of SP was not significantly associated with either particular months of the year or seasons. After adjusting for seasonality, month and time trends, relative humidity was positively associated with the monthly incidence of SP among men, while ambient temperature and rainfall were significantly associated with SP events among women. However, changes in monthly atmospheric pressure did not appear to influence the monthly risk of SP. CONCLUSIONS: These results do not support the premise that seasonal factors are involved in precipitating SP, although certain climatic parameters showed weak associations with the incidence of SP. Future studies should investigate other combinations of weather phenomena and potential triggering factors, in order to shed light on the occurrence of SP in various regions and climatic conditions, and among both men and women.

Disruption of retinoid homeostasis induces RBP4 overproduction in diabetes: O-GlcNAcylation involved.

BACKGROUND: Retinol-binding protein 4 (RBP4) is elevated and associated with inflammation in metabolic diseases. Disruption of the retinol cascade and O-GlcNAcylation of the RBP4 receptor (STRA6) are found in diabetic kidneys. OBJECTIVES: We investigated whether the disruption of the retinol cascade induces RBP4 overproduction and if O-linked GlcNAc modification targets RBPR2 and contributes to the disruption of retinol cascades in diabetic livers. METHODS: Western blot or immunohistochemistry for RBPR2, CRBP1, LRAT, RALDH, RARα, RARγ, RXRα, RBP4, GFAT, OGT, OGA and inflammatory markers, as well as ELISA for RBP4, were performed in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. Immunoprecipitation and dual fluorescence staining were used to explore O-GlcNAc-modified RBPR2 and RBP4 binding activity on RBPR2. Transfection of the CRBP1 gene was done to verify whether a disrupted retinol cascade induces RBP4 overproduction. OGT silencing was done to investigate the association of O-GlcNAcylation with the disruption of retinol cascade. RESULTS: Disruption of retinol cascade, RBP4 overproduction, O-GlcNAcylation of RBPR2, decreased RBP4 binding activity on RBPR2 and inflammation were found in livers of db/db and ob/ob mice and high glucose-cultured hepatocytes. CRBP1 gene transfection reversed the suppression of the cellular retinol cascade and simultaneously attenuated the RBP4 overproduction and inflammation in high glucose-treated hepatocytes. The silencing of OGT reversed the disruption of the cellular retinol cascade, RBP4 overproduction and inflammation induced by high glucose in hepatocytes. CONCLUSIONS: This study indicates that the disruption of cellular retinol cascade is strongly associated with RBP4 overproduction and inflammation in diabetic livers. RBPR2 is one target for high glucose-mediated O-linked GlcNAc modification, which causes liver retinol dyshomeostasis.

Electronegative low-density lipoprotein of patients with metabolic syndrome induces pathogenesis of aorta through disruption of the stimulated by retinoic acid 6 cascade.

AIMS/INTRODUCTION: Electronegative low-density lipoprotein (L5) is the most atherogenic fraction of low-density lipoprotein and is elevated in people with metabolic syndrome (MetS), whereas the retinol-binding protein 4 receptor (stimulated by retinoic acid 6 [STRA6]) cascade is disrupted in various organs of patients with obesity-related diseases. Our objective was to investigate whether L5 from MetS patients capably induces pathogenesis of aorta through disrupting the STRA6 cascade. MATERIAL AND METHODS: We examined the in vivo and in vitro effects of L5 on the STRA6 cascade and aortic atherogenic markers. To investigate the role of this cascade on atherosclerotic formation, crbp1 transfection was carried out in vitro. RESULTS: This study shows that L5 activates atherogenic markers (p38 mitogen-activated protein kinases, pSmad2 and matrix metallopeptidase 9) and simultaneously suppresses STRA6 signals (STRA6, cellular retinol-binding protein 1, lecithin-retinol acyltransferase, retinoic acid receptor-α and retinoid X receptor-α) in aortas of L5-injected mice and L5-treated human aortic endothelial cell lines and human aortic smooth muscle cell lines. These L5-induced changes of the STRA6 cascade and atherogenic markers were reversed in aortas of LOX1-/- mice and in LOX1 ribonucleic acid-silenced human aortic endothelial cell lines and human aortic smooth muscle cell lines. Furthermore, crbp1 gene transfection reversed the disruption of the STRA6 cascade, the phosphorylation of p38 mitogen-activated protein kinases and Smad2, and the elevation of matrix metallopeptidase 9 in L5-treated human aortic endothelial cell lines. CONCLUSIONS: This study shows that L5 from MetS patients induces atherogenic markers by disrupting STRA6 signaling. Suppression of STRA6 might be one novel pathogenesis of aorta in patients with MetS.

Local action of endogenous renal tubular atrial natriuretic peptide.

Up-regulation of atrial natriuretic peptide (ANP) mRNA in the kidneys in several disorders has been demonstrated; however, evidence that ANP synthesized by the kidney exerts a local function has never been produced. Therefore, we investigated whether endogenous ANP could modulate high glucose-stimulated TGF-beta1, collagen type I and nuclear factor-kappaB (NF-kappaB) in NRK-52E cells using transfection of ANP and ANP small interfering RNA (siANP). NRK-52E cells were grown with or without transfection with ANP plasmid; cells were also transfected with ANP siRNA or control siRNA. These cells were then stimulated with a high glucose concentration to modulate ANP, TGF-beta1, collagen type I, NF-kappaB and IkappaB-alpha, and the results showed that ANP, TGF-beta1, collagen type I and NF-kappaB significantly increased in untransfected cells, and the transfection of ANP significantly attenuated high glucose-activated TGF-beta1, collagen I and NF-kappaB expression. ANP siRNA knocked-down ANP but significantly increased TGF-beta1 and collagen I under normal glucose conditions; ANP siRNA decreased IkappaB-alpha but strongly enhanced high glucose-activated TGF-beta1, collagen type I and NF-kappaB. In contrast, medium from ANP-transfected cells attenuated high glucose-activated TGF-beta1 and collagen type I expression in NRK-52E cells transfected with siANP. In conclusion, our results demonstrated that siANP increased activation of TGF-beta1, collagen type I and NF-kappaB in NRK-52E cells under high glucose conditions, and medium from ANP-transfected cells attenuated high glucose-activated TGF-beta1 and collagen type I. This is the first study to demonstrate the auto/paracrine action of endogenous ANP in renal tubular cells on the attenuation of hyperglycemia-activated TGF-beta1 and NF-kappaB expression. J. Cell. Physiol. 219: 776-786, 2009. (c) 2009 Wiley-Liss, Inc.

Negative Association of Proton Pump Inhibitors With Subsequent Development of Breast Cancer: A Nationwide Population-Based Study.

Although current evidence suggests potential antitumor activity of proton pump inhibitors (PPIs), there is no population-based evidence of an association between PPI use and subsequent breast cancer risks. We used an observational case-control study to examine the association between prior PPI use and breast cancer occurrence. Additional analysis examined dose-response and age-stratified associations of PPIs with breast cancer. This study used data from the Taiwan National Health Insurance Research Dataset. A total of 64,234 women diagnosed with breast cancer between 2004 and in 2013 were selected as cases. Controls were 64,234 women without cancer who were selected by matching them with cases on the basis of sociodemographic characteristics and widely prevalent comorbidities. Each study subject's claims data were tracked back for 5 years to determine precancer prescriptions of PPIs. Logistic regression modeling was used for the analysis. A total of 11,871 (9.24%) women had used PPIs within the prior 5 years, 8.06% and 10.42% among cases and controls, respectively. Breast cancer patients were 25% less likely to have had prior PPI exposure after adjustment for comorbidities that predispose to PPI exposure (95%CI 0.72-0.78) in the risk of breast cancer occurrence. A dose-response effect was also detected, with the highest effect, 35% lower PPI odds (95%CI 0.61-0.70) among patients in the highest exposure category. Our findings may suggest that women at a higher-than-average risk of breast cancer may benefit from PPI prescriptions if they have medical conditions that could benefit from PPIs.

O-GlcNAcylation disrupts STRA6-retinol signals in kidneys of diabetes.

BACKGROUND: O-GlcNAcylation is an important mechanism of diabetic complication. Retinoid homeostasis regulates cell-physiological functions through STRA6-retinol signaling. Therefore, we investigated whether O-GlcNAcylation disrupted STRA6-retinol signals in diabetes. METHODS: Immunoprecipitation and proximity ligation assay were used to investigate O-GlcNAcylation of STRA6-retinol signals in kidneys of db/db and ob/ob mice. Western blot and immunohistochemistry were done for STRA6/CRBP1/LRAT/RALDH1/RARs pathway, GFAT, OGT, TGFß1 and collagen 1 level. HPLC and ELISA for retinol, retinal, and retinoic acid concentrations were performed in vivo and vitro. RBP4 binding with STRA6 was measured in vitro. To verify whether O-GlcNAcylation disrupted STRA6-retinol signals, treatment of TMG and OSMI-1, transfection of OGA and OGT, and OGT siRNA were performed in HK-2 cells. RESULTS: STRA6 and RALDH1 were highly O-GlcNAc-modified in glomeruli and tubules of db/db and ob/ob mice. RBP4, p-Try, p-JAK2, and p-STAT5 on STRA6 immunoprecipitate were reduced. Cellular retinol signals (CRBP1, LRAT, ADH, retinol, retinal, RA, RARα, RARγ and RXRα) remarkably decreased in kidneys of db/db, ob/ob mice and HG-cultured cells. TMG and OGT transfection induced O-GlcNAcylation of STRA6 and RALDH1, repressed RBP4-bound STRA6, and retinol signals in NG-cultured cells. OSMI-1, OGA transfection, and OGT silence reversed O-GlcNAc-modification of STRA6 and RALDH1, and rescued the decrease of retinol signals, and reversed the increase of TGFß1 and collagen 1 in HG-treated cells. CONCLUSIONS: O-GlcNAcylation significantly modified STRA6 and RALDH1, suppressed RBP4 binding activity, and disrupted retinol signals in the kidney of diabetes. GENERAL SIGNIFICANCE: This study first indicates that STRA6-retinol signals were directly disrupted by O-GlcNAcylation in diabetic kidney.

Fewer acute respiratory infection episodes among patients receiving treatment for gastroesophageal reflux disease.

Patients with gastroesophageal reflux disease (GERD) present with comorbid complications with implications for healthcare utilization. To date, little is known about the effects of GERD treatment with a proton-pump inhibitor (PPI) on patients' subsequent healthcare utilization for acute respiratory infections (ARIs). This population-based study compared ARI episodes captured through outpatient visits, one year before and one year after GERD patients received PPI treatment. We used retrospective data from the Longitudinal Health Insurance Database 2005 in Taiwan, comparing 21,486 patients diagnosed with GERD from 2010 to 2012 with 21,486 age-sex matched comparison patients without GERD. Annual ARI episodes represented by ambulatory care visits for ARI (visits during a 7-day period bundled into one episode), were compared between the patient groups during the 1-year period before and after the index date (date of GERD diagnosis for study patients, first ambulatory visit in the same year for their matched comparison counterpart). Multiple regression analysis using a difference-in-difference approach was performed to estimate the adjusted association between GERD treatment and the subsequent annual ARI rate. We found that the mean annual ARI episode rate among GERD patients reduced by 11.4%, from 4.39 before PPI treatment, to 3.89 following treatment (mean change = -0.5 visit, 95% confidence interval (CI) = (-0.64, -0.36)). In Poisson regression analysis, GERD treatment showed an independent association with the annual ARI rate, showing a negative estimate (with p<0.001). The study suggests that GERD treatment with PPIs may help reduce healthcare visits for ARIs, highlighting the importance of treatment-seeking by GERD patients and compliance with treatment.

Association of Alzhemier's disease with hepatitis C among patients with bipolar disorder.

Associations of hepatitis C virus infection with Alzheimer's disease have not been studied among higher risk, bipolar disorder patients. This population-based case-control study investigated the risks of hepatitis C virus infection among Alzheimer's disease patients with bipolar disorder in the years preceding their Alzheimer's disease diagnosis. We used 2000-2013 data from the Longitudinal Health Insurance Database in Taiwan. Among patients with bipolar disorder, 73 were diagnosed with Alzheimer's disease (cases), who were compared with 365 individuals with bipolar disorder but without Alzheimer's disease (randomly selected controls matched on sex, age, and index year with cases). Prior claims (before the diagnosis year/index year for controls) were screened for a diagnosis of hepatitis C virus infection. Conditional logistic regression models were used for analysis. We found that 23 (31.51%) and 60 (16.44%) patients with bipolar disease were identified with a hepatitis C diagnosis among those with and without Alzheimer's disease, respectively. Compared to controls, patients with Alzheimer's disease showed 2.31-fold (95% confidence interval = 1.28-4.16) increased risk of hepatitis C infections adjusted for demographics and socio-economic status. Findings suggest an association of Alzheimer's disease with a preceding diagnosis of hepatitis C infection among patients with bipolar disorder. Findings may suggest a need for increased awareness of and appropriate surveillance for Alzheimer's disease in patients with bipolar disorder diagnosed with hepatitis C infection.