Bidirectional association between infectious gastroenteritis and inflammatory bowel disease: a population-based study.

BACKGROUND: Intertwined association between infectious gastroenteritis (IGE) and inflammatory bowel disease (IBD) has not been investigated clearly. We aimed to examine the bidirectional association between IGE and IBD. METHODS: A bidirectional study using the Taiwan National Health Insurance Research Database was designed. Through a case-control design, we identified 2899 new IBD cases during 2006-2017 and matched to 28,990 non-IBD controls. We used conditional logistic regression model to estimate odds ratios (OR) of IBD for previous IGE in different exposure time-windows within 5-years before IBD diagnosis and Poisson regression model to estimate incidence rate ratio (IRR) of subsequent IGE for IBD group to non-IBD group. RESULTS: The mean age at the initial IBD diagnosis was 41 years. More IBD patients (21.49%) than controls (12.60%) had been exposed to IGE during > 6 months to 5 years before IBD diagnosis, the OR of IBD for IGE was 1.89 [95% confidence interval: 1.69-2.11]. Excess OR decreased as IGE exposure time before the index date increased. More IGE episodes were associated with additional increase in IBD risk (OR: 1.64, 2.19, 2.57, 3.50, and 4.57 in patients with 1, 2, 3, 4, and ≥ 5 IGE episodes, respectively). The IRR of having IGE for IBD group to non-IBD group was 2.42 before IBD diagnosis and increased to 5.74 after IBD diagnosis. CONCLUSIONS: These findings suggested an IGE-IBD bidirectional association. More attention is needed for physicians to develop preventive strategies and be aware of the higher risk of subsequent IGE in IBD patients.

Safety of ChAdOx1 nCoV-19 vaccination in patients with end-stage renal disease on hemodialysis.

BACKGROUND: COVID-19 vaccination is essential. However, no study has reported adverse events (AEs) after ChAdOx1 nCoV-19 vaccination in patients with end-stage renal disease (ESRD) on hemodialysis (HD). This study investigated the AEs within 30-days after the first dose of ChAdOx1 nCoV19 (Oxford-AstraZeneca) in ESRD patients on HD. METHODS AND FINDINGS: A total of 270 ESRD patients on HD were enrolled in this study. To determine the significance of vascular access thrombosis (VAT) post vaccination, we performed a self-controlled case study (SCCS) analysis. Of these patients, 38.5% had local AEs; local pain (29.6%), tenderness (28.9%), and induration (15.6%) were the most common. Further, 62.2% had systemic AEs; fatigue (41.1%), feverishness (20%), and lethargy (19.9%) were the most common. In addition, post-vaccination thirst affected 18.9% of the participants with female predominance. Younger age, female sex, and diabetes mellitus were risk factors for AEs. Five patients had severe AEs, including fever (n = 1), herpes zoster (HZ) reactivation (n = 1), and acute VAT (n = 3). However, the SCCS analysis revealed no association between vaccination and VAT; the incidence rate ratio (IRR)-person ratio was 0.56 (95% CI 0.13-2.33) and 0.78 (95% CI 0.20-2.93) [IRR-event ratio 0.78 (95% CI 0.15-4.10) and 1.00 (95% CI 0.20-4.93)] in the 0-3 months and 3-6 months period prior to vaccination, respectively. CONCLUSIONS: Though some ESRD patients on HD had local and systemic AEs after first-dose vaccination, the clinical significance of these symptoms was minor. Our study confirmed the safety profile of ChAdOx1 nCoV-19 in HD patients and presented a new viewpoint on vaccine-related AEs. The SCCS analysis did not find an elevated risk of VAT at 1 month following vaccination. Apart from VAT, other vaccine-related AEs, irrespective of local or systemic symptoms, had minor clinical significance on safety issues. Nonetheless, further coordinated, multi-center, or registry-based studies are needed to establish the causality.

Increased risk of type 2 diabetes in patients with systemic lupus erythematosus: A nationwide cohort study in Taiwan.

Data on the risk of developing diabetes in patients with systemic lupus erythematosus (SLE) are limited and have yielded mixed results. We conducted a nationwide cohort study to investigate the risk of subsequent type 2 diabetes in patients with SLE compared with matched non-SLE controls. Data were collected from the Taiwan National Health Insurance Research Database. Adult patients newly diagnosed with SLE between 2003 to 2010 were identified as the study cohort. The non-SLE group was matched for age, gender, and date of initial diagnosis as the comparison cohort. A total of 6159 SLE patients (87.90% female, mean age 38.79 years) were identified during this period. Of these, 206 (3.34%) developed type 2 diabetes. The 3-year incidence of type 2 diabetes was significantly higher in the SLE cohort than in the control group (130.26 vs 101.18 cases per 10,000 person-years), with an adjusted hazard ratio of 1.22 (95% confidence interval [CI] 1.04-1.44), after adjusting for age, gender, underlying comorbidities, and monthly income. Stratified analyses showed that women with SLE and low-income SLE patients (monthly income < 20,000 New Taiwan Dollar) had a higher risk of type 2 diabetes than non-SLE controls, with adjusted hazard ratios of 1.21 (95% CI 1.01-1.45) and 1.36 (95% CI 1.10-1.69), respectively. Patients with newly diagnosed SLE had a 22% increased risk of developing type 2 diabetes during the 3-year follow-up period compared with matched controls.

Roles of reactive oxygen species, mitochondrial membrane potential, and p53 in evodiamine-induced apoptosis and G2/M arrest of human anaplastic thyroid carcinoma cells.

BACKGROUND: Our previous studies have shown that evodiamine (EVO) as paclitaxel and nocodazole could trigger apoptosis in various human cancer cells including human renal cell carcinoma cells, colorectal carcinoma cells, and glioblastoma cells. This study aims to investigate the anti-cancer effects of EVO on human anaplastic thyroid carcinoma (ATC) cells, and underlining mechanism. METHODS: Two different endogenous p53 status human anaplastic thyroid carcinoma (ATC) cells including SW1736 (wtp53) and KAT4B (mutp53) were applied in the present study. The cytotoxicity of EVO on ATC cells was measured by MTT assay, and apoptosis and G2/M arrest were detected by propidium iodide (PI) staining followed by flow cytometry. Expression of indicated proteins was evaluated by Western blotting analysis, and pharmacological studies using chemical inhibitors and siRNA were performed for elucidating underlying mechanism. The roles of mitochondrial membrane potential and reactive oxygen species were investigated by flow cytometry using DiOC6 and DCFH-DA dye, respectively. RESULTS: SW1736 (wtp53) cells showed a higher apoptotic percentage than KAT4B (mutp53) cells in response to EVO stimulation via a flow cytometric analysis. Mechanistic studies showed that increased p53 and its downstream proteins, and disrupted MMP with increased intracellular peroxide production participated in EVO-induced apoptosis and G2/M arrest of SW1736 cells. In EVO-treated KAT4B cells, significant increases in G2/M percentage but little apoptotic events by EVO was observed. Structure-activity analysis showed that an alkyl group at position 14 was critical for induction of apoptosis related to ROS production and MMP disruption in SW1736 cells. CONCLUSION: Evidence indicated that the endogenous p53 status affected the sensitivity of ATC cells to EVO-induced apoptosis and G2/M arrest, revealing the potential role of p53 related to increased ROS production and disrupted MMP in the anticancer actions of EVO, and alkylation at position 14 of EVO is a critical substitution for apoptosis of ATC cells.

Site-specific mortality in native joint septic arthritis: a national population study.

OBJECTIVE: This national cohort study investigated the incidence, site-specific mortality and prognostic factors of native septic arthritis (SA). METHODS: Tapping Taiwan's National Health Insurance Research Database, we identified inpatients with newly diagnosed SA between 1998 and 2012. They were categorized by site of infection and followed to calculate 30-day, 90-day and 1-year mortality. Predictors of mortality were calculated using Cox models. RESULTS: A total of 31 491 patients were identified as having SA, the most common site of infection being the knee (50.1%), followed by the hip (14.4%), other sites (26.8%), the shoulder (5.5%) and multiple sites (1.2%). Knee joint involvement was the most common site for all subgroups. Incidence increased from 9.8/105 in 1998 to 13.3/105 in 2012. The 30-day, 90-day and 1-year mortality rates were 4.3, 8.6 and 16.4% respectively. Predictors for mortality were hip infection, shoulder infection, multiple-site infection, being male, age ≥65 years old and comorbidities. We derived a mortality scoring model over age/SA site/comorbidity, and age ≥65 years old had the greatest risk contribution to mortality. No matter whether 1-month, 3-month or 1-year mortality was being considered, patients with the higher risk scores had the higher mortality rates (P < 0.0001). CONCLUSION: SA is an emerging infectious disease with a rising incidence, long duration of hospital stay and high mortality rate. The most common affected joint was knee for all subgroups. Patients aged ≥65 years old had a high SA incidence and the greatest risk contribution.

Effect of Chronic Pancreatitis on Complications and Mortality in DM Patients: A 10-year Nationwide Cohort Study.

CONTEXT: Chronic pancreatitis (CP), is a long-term inflammation of the pancreatic parenchyma, and might increase risk of a hyperglycemia crisis or hypoglycemia in patients with diabetes mellitus (DM); however, the relationship has not been previously investigated. OBJECTIVE: To investigate the risk of diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), hypoglycemia, and long-term outcomes in DM patients with CP. DESIGN: A population-based cohort study. SETTING AND PARTICIPANTS: Tapping Taiwan's National Health Insurance Research Database, we identified 506 DM patients with newly diagnosed CP from 1999 to 2010 and created a control cohort consisting of 5060 age- and sex-matched DM patients without CP from the same time period. We followed those 2 cohorts from the index date to occurrence of outcomes, the date of death or 31 December 2012. MAIN OUTCOME MEASURES: DKA, HHS, hypoglycemia and mortality. RESULTS: DM patients with CP, who were predominantly male (88%) and younger (60% < 45 years old), had a 9.5-, 5.0-, and 3.0-fold higher risk for DKA (95% confidence interval [CI]: 6.51-13.91), HHS (95% CI: 2.85-8.62), and hypoglycemia (95% CI: 2.23-4.08), respectively. They also had lower 1-, 5-, and 10-year cumulative survival rates (98.4% vs 99.0%, 87.7% vs 96.6%, and 78.7% vs 93.6%, respectively) (log-rank test: P < .001), and a 2.43-fold higher risk for death (HR: 2.43, 95% CI: 1.82-3.27). CONCLUSIONS: In Taiwan, DM patients with CP have a higher incidence of DKA, HHS, hypoglycemia, and mortality. More attention is needed for preventing hyperglycemia crisis and hypoglycemia prevention in this population.

Warning signs and severe dengue in end stage renal disease dialysis patients.

BACKGROUND/PURPOSE: The 2009 WHO guideline established warning signs (WS) to predict severe dengue (SD). However, their positive predictive value has been found to be low in the general adult population, but they might be higher in a different population. This study investigated the association between WS and SD in end stage renal disease (ESRD) patients on maintenance dialysis in Taiwan where both diseases are prevalent. METHODS: This study enrolled ESRD dialysis patients with dengue in 2015. Demographic, laboratory data, symptoms/signs and complication of dengue were retrospectively collected from medical records at our hospital. RESULTS: Of 49 ESRD patients with dengue, 44 patients were receiving hemodialysis and 5 peritoneal dialysis. Older patients (>65 years old) tended to have the WS(56% vs 16.7%, P = 0.007). The rate of hospitalization, intensive care unit admission and in-hospital mortality was 79.6%, 22.5%, and 8.2%, respectively. Eighteen patients (36.7%) presented WS and eighteen patients (36.7%) developed to SD, including ten with plasma leakage, twelve with hemorrhage, and six with organ failure. Patients with WS were seven times more likely to develop SD than those without (OR: 7.06; 95%CI: 1.34-37.21). WS was associated with plasma leakage (OR: 12.36; 95% CI: 1.56-97.74) and severe hemorrhage (OR: 5.1; 95% CI: 1.03-25.18), but not organ failure. CONCLUSIONS: Prevalence of SD is high in ESRD dialysis patients. The presence of WSs in this group was highly correlated with SD. Thus, more attention should be paid to treating ESRD patients with dengue fever if they present WSs.

Pro-apoptotic effect of haem oxygenase-1 in human colorectal carcinoma cells via endoplasmic reticular stress.

Several biological effects of haem oxygenase (HO)-1, including anti-inflammatory, antiapoptotic and antioxidative properties were reported; however, the role of HO-1 in apoptosis is still unclear. In the presence of stimulation by cobalt protoporphyrin (CoPP), an HO-1 inducer, apoptotic characteristics were observed, including DNA laddering, hypodiploid cells, and cleavages of caspase (Casp)-3 and poly(ADP) ribose polymerase (PARP) proteins in human colon carcinoma COLO205, HCT-15, LOVO and HT-29 cells in serum-free (SF) conditions with increased HO-1, but not heat shock protein 70 (HSP70) or HSP90. The addition of 10% foetal bovine serum (FBS) or 1% bovine serum albumin accordingly inhibited CoPP-induced apoptosis and HO-1 protein expression in human colon cancer cells. CoPP-induced apoptosis of colon cancer cells was prevented by the addition of the pan-caspase inhibitor, Z-VAD-FMK (VAD), and the Casp-3 inhibitor, Z-DEVD-FMK (DEVD). N-Acetyl cysteine inhibited reactive oxygen species-generated H2 O2 -induced cell death with reduced intracellular peroxide production, but did not affect CoPP-induced apoptosis in human colorectal carcinoma (CRC) cells. Two CoPP analogs, ferric protoporphyrin and tin protoporphyrin, did not affect the viability of human CRC cells or HO-1 expression by those cells, and knockdown of HO-1 protein expression by HO-1 small interfering (si)RNA reversed the cytotoxic effect elicited by CoPP. Furthermore, the carbon monoxide (CO) donor, CORM, but not FeSO4 or biliverdin, induced DNA ladders, and cleavage of Casp-3 and PARP proteins in human CRC cells. Increased phosphorylated levels of the endoplasmic reticular (ER) stress proteins, protein kinase R-like ER kinase (PERK), and eukaryotic initiation factor 2α (eIF2α) by CORM and CoPP were identified, and the addition of the PERK inhibitor, GSK2606414, inhibited CORM- and CoPP-induced apoptosis. Increased GRP78 level and formation of the HO-1/GRP78 complex were detected in CORM- and CoPP-treated human CRC cells. A pro-apoptotic role of HO-1 against the viability of human CRC cells via induction of CO and ER stress was firstly demonstrated herein.

Activation of PERK Contributes to Apoptosis and G2/M Arrest by Microtubule Disruptors in Human Colorectal Carcinoma Cells ‡.

Microtubule-targeting agents (MTAs) are widely used in cancer chemotherapy, but the therapeutic responses significantly vary among different tumor types. Protein kinase RNA-like endoplasmic reticular (ER) kinase (PERK) is an ER stress kinase, and the role of PERK in the anticancer effects of MTAs is still undefined. In the present study, taxol (TAX) and nocodazole (NOC) significantly induced apoptosis with increased expression of phosphorylated PERK (pPERK; Tyr980) in four human colon cancer cell lines, including HCT-15, COLO205, HT-20, and LOVO cells. Induction of G2/M arrest by TAX and NOC with increases in phosphorylated Cdc25C and cyclin B1 protein were observed in human colon cancer cells. Application of the c-Jun N-terminal kinase (JNK) inhibitors SP600125 (SP) and JNK inhibitor V (JNKI) significantly reduced TAX- and NOC-induced apoptosis and G2/M arrest of human colon cancer cells. Interestingly, TAX- and NOC-induced pPERK (Tyr980) protein expression was inhibited by adding the JNK inhibitors, SP and JNKI, and application of the PERK inhibitor GSK2606414 (GSK) significantly reduced apoptosis and G2/M arrest by TAX and NOC, with decreased pPERK (Tyr980) and pJNK, phosphorylated Cdc25C, and Cyc B1 protein expressions in human colon cancer cells. Decreased viability by TAX and NOC was inhibited by knockdown of PERK using PERK siRNA in COLO205 and HCT-15 cells. Disruption of the mitochondrial membrane potential and an increase in B-cell lymphoma-2 (Bcl-2) protein phosphorylation (pBcl-2; Ser70) by TAX and NOC were prevented by adding the PERK inhibitor GSK and JNK inhibitor SP and JNKI. A cross-activation of JNK and PERK by TAX and NOC leading to anti-CRC actions including apoptosis and G2/M arrest was first demonstrated herein.

Is insomnia a risk factor for new-onset asthma? A population-based study in Taiwan.

OBJECTIVES: To determine whether insomnia at baseline is a risk factor for new-onset asthma. METHODS: We recruited 48 871 patients with insomnia (insomnia group) newly diagnosed between 2002 and 2007, and 97 742 matched controls without insomnia (control group) from Taiwan's Longitudinal Health Insurance Database 2000. All of the patients were followed up for 4 years to see whether new-onset asthma developed. Patients with previous asthma or insomnia were excluded. The Poisson regression was used to estimate the incidence rate ratios (IRRs) and 95% CIs of asthma. Cox proportional hazard regression was used to calculate the risk of asthma between the two groups. RESULTS: After a 4-year follow-up, 424 patients in the insomnia group and 409 in the control group developed asthma. The incidence rate of asthma was significantly higher in the insomnia group (22.01vs10.57 per 10 000 person-years). Patients with insomnia have a higher risk of developing new-onset asthma during the 4-year follow-up (HR: 2.08, 95% CI 1.82 to 2.39). The difference remained significant after adjustment (adjusted HR: 1.89, 95% CI 1.64 to 2.17). CONCLUSIONS: This large population-based study suggests that insomnia at baseline is a risk factor for developing asthma.

Hispolon Suppresses LPS- or LTA-Induced iNOS/NO Production and Apoptosis in BV-2 Microglial Cells.

Hispolon (HIS) is an active polyphenol compound derived from Phellinus linteus (Berkeley & Curtis), and our previous study showed that HIS effectively inhibited inflammatory responses in macrophages [Yang, L.Y., S.C. Shen, K.T. Cheng, G.V. Subbaraju, C.C. Chien and Y.C. Chen. Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages. J. Ethnopharmacol. 156: 61-72, 2014]; however, its effect on neuronal inflammation is still undefined. In this study, HIS concentration- and time-dependently inhibited lipopolysaccharide (LPS)- and lipoteichoic acid (LTA)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production with increased heme oxygenase (HO)-1 proteins in BV-2 microglial cells. Accordingly, HIS protected BV-2 cells from LPS- or LTA-induced apoptosis, characterized by decreased DNA ladder formation, and caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage in BV-2 cells. Similarly, the NOS inhibitor, N-nitro-L-arginine methyl ester (NAME), inhibited LPS- or LTA-induced apoptosis of BV-2 cells, but neither NAME nor HIS showed any inhibition of NO production or cell death induced by the NO donor, sodium nitroprusside (SNP), indicating the involvement of NO in the inflammatory apoptosis of microglial cells. Activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-[Formula: see text]B contributed to LPS- or LTA-induced iNOS/NO production and apoptosis of BV-2 cells, and that was suppressed by HIS. Additionally, HIS possesses activity to induce HO-1 protein expression via activation of extracellular signal-regulated kinase (ERK) in BV-2 cells, and application of the HO inhibitor, tin protoporphyrin (SnPP), or knockdown of HO-1 protein by HO-1 small interfering (si)RNA significantly reversed HIS inhibition of NO production and cell death in BV-2 cells stimulated by LPS. Results of an analysis of the effects of HIS and two structurally related chemicals, i.e. dehydroxy-HIS (D-HIS) and HIS-methyl ester (HIS-ME), showed that HIS expressed the most potent inhibitory effects on iNOS/NO production, JNK activation, and apoptosis in BV-2 microglial cells activated by LPS with increased HO-1 protein expression. Overall these results suggested that HIS possesses inhibitory activity against LPS- or LTA-induced inflammatory responses including iNOS/NO production and apoptosis in BV-2 microglial cells and that the mechanisms involve upregulation of the HO-1 protein and downregulation of JNK/NF-[Formula: see text]B activation. A critical role of hydroxyl at position C3 in the anti-inflammatory actions of HIS against activated BV-2 microglial cells was suggested.

Risk of serous retinal detachment in patients with end-stage renal disease on dialysis.

The aim of this retrospective, nationwide, matched cohort study was to investigate the association of serous retinal detachment with having end-stage renal disease (ESRD) while on dialysis. The cohort study included 94,024 patients with ESRD on dialysis registered between January 2000 to December 2009 in the Taiwan National Health Insurance Research Database. An age- and sex-matched control group comprised 94,024 patients selected from the Taiwan Longitudinal Health Insurance Database 2000. Information for each patient was collected from the index date until December 2011. Twenty-seven ESRD patients and 11 controls developed serous retinal detachment (P < 0.001) during follow-up, demonstrating a significantly increased risk of serous retinal detachment in patients with ESRD on dialysis compared with controls (incidence rate ratio = 3.39, 95% confidence interval [CI] = 1.68-6.83). After adjustment for potential confounders, patients were 3.86 times more likely to develop serous retinal detachment than the full cohort (adjusted HR = 3.86, 95% CI = 1.15-12.96). In conclusion, patients with ESRD on dialysis demonstrate an increased risk of serous retinal detachment. Interdisciplinary collaboration between nephrologists and ophthalmologists is important to deal with serous retinal detachment in patients with ESRD on dialysis and prevent impairments of visual acuity.

Evodiamine Prevents Glioma Growth, Induces Glioblastoma Cell Apoptosis and Cell Cycle Arrest through JNK Activation.

Evodiamine (EVO) is an active medicinal compound derived from the traditional herbal medicine Evodia rutaecarpa. It has been reported that evodiamine has several beneficial biological properties, including anticancer and anti-inflammatory activities. However, the in vitro and in vivo anticancer activities of EVO against the growth of glioblastoma cells remain undefined. EVO induced significant decreases in the viability of U87 and C6 glioma cells, but not of primary astrocytes, according with the occurrence of apoptotic characteristics including DNA ladders, caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage, and hypodiploid cells. The disruption of the mitochondrial membrane potential (MMP) was detected, and it was found that the peptidyl caspase-9 inhibitor, Z-LEHD-FMK, significantly prevented glioma cells from EVO-induced apoptosis. Increased c-Jun N-terminal kinase (JNK) protein phosphorylation by EVO was observed, and the addition of JNK inhibitors, SP600125 and JNKI inhibited the EVO-induced apoptosis was inhibited. Additionally, EVO treatment induced G2/M arrest with increased polymerized tubulin protein expression in U87 and C6 cells. Elevated expressions of the cyclin B1, p53, and phosphorylated (p)-p53 proteins were detected in EVO-treated glioma cells, and these were inhibited by JNK inhibitors. An in vivo study showed that EVO significantly reduced the growth of gliomas elicited by the subcutaneous injection of U87 cells with increases in cyclin B1, p53, and p-p53 protein expressions in tumors. An analysis of eight EVO-related chemicals showed that alkyl groups at position 14 in EVO are important for its anti-glioma effects which involve both apoptosis and G2/M arrest. Evidence is provided that supports EVO induction of apoptosis and G2/M arrest via the activation of JNK-mediated gene expression and disruption of MMP in glioblastoma cells. EVO was shown to penetrate the blood-brain barrier; EVO is therefore predicted to be a promising compound for the chemotherapy of glioblastomas and deserves further investigations.

Epidemiology and outcomes of hypoglycemia in patients with advanced diabetic kidney disease on dialysis: A national cohort study.

BACKGROUND: Patients with advanced diabetic kidney disease (DKD) behave differently to diabetic patients without kidney disease. We aimed to investigate the associations of hypoglycemia and outcomes after initiation of dialysis in patients with advanced DKD on dialysis. METHODS: Using National Health Insurance Research Database, 20,845 advanced DKD patients beginning long-term dialysis between 2002 and 2006 were enrolled. We investigated the incidence of severe hypoglycemia episodes before initiation of dialysis. Patients were followed from date of first dialysis to death, end of dialysis, or 2008. Main outcomes measured were all-cause mortality, myocardial infarction (MI), and subsequent severe hypoglycemic episodes after dialysis. RESULTS: 19.18% patients had at least one hypoglycemia episode during 1-year period before initiation of dialysis. Advanced DKD patients with higher adapted Diabetes Complications Severity Index (aDCSI) scores were associated with more frequent hypoglycemia (P for trend < 0.001). Mortality and subsequent severe hypoglycemia after dialysis both increased with number of hypoglycemic episodes. Compared to those who had no hypoglycemic episodes, those who had one had a 15% higher risk of death and a 2.3-fold higher risk of subsequent severe hypoglycemia. Those with two or more episodes had a 19% higher risk of death and a 3.9-fold higher risk of subsequent severe hypoglycemia. However, previous severe hypoglycemia was not correlated with risk of MI after dialysis. CONCLUSIONS: The rate of severe hypoglycemia was high in advanced DKD patients. Patients with higher aDCSI scores tended to have more hypoglycemic episodes. Hypoglycemic episodes were associated with subsequent hypoglycemia and mortality after initiation of dialysis. We studied the associations and further study is needed to establish cause. In addition, more attention is needed for hypoglycemia prevention in advanced DKD patients, especially for those at risk patients.

Bidirectional association between ESRD dialysis and diabetes: National cohort study.

BACKGROUND: Diabetes is associated with development of end-stage renal disease (ESRD) dialysis, but it is not clear whether ESRD dialysis is a risk factor for new-onset diabetes (NODM). METHODS: Using the Taiwan National Health Insurance Research Database, we designed two cohort studies to determine the association between dialysis and diabetes. Analysis 1 estimated the hazard ratios (HR) of ESRD dialysis in 20,585 patients with type 2 diabetes (T2DM) and 82,340 gender- and age- matched controls without diabetes. Analysis 2 estimated the HRs of NODM in 18,489 ESRD patients undergoing dialysis and 73,956 gender- and age- matched controls without ESRD dialysis. The follow-up period was from 2000 to date of endpoint, the date of death, or December 31, 2008. Cox proportional models were used to estimate the relative hazards. RESULTS: In analysis 1, the incidence of ESRD dialysis was higher in the T2DM cohort than in the non-diabetes cohort (6.78 vs. 0.61 per 1,000 person-years; HR: 7.97; 95%CI: 7.05-8.00). In analysis 2, the incidence of NODM was higher in the ESRD dialysis cohort than in the without-ESRD dialysis cohort (22.84 vs. 13.99 per 1,000 person-years; HR: 1.40; 95% CI: 1.34-1.47). CONCLUSIONS: ESRD dialysis and diabetes were bidirectionally associated. The relationship between T2DM and incident ESRD dialysis was much stronger than between ESRD dialysis and NODM. Further studies are needed to determine the mechanism of ESRD dialysis-related NODM.

Epidemiology of cancer in end-stage renal disease dialysis patients: a national cohort study in Taiwan.

The incidence and mortality of site-specific cancers in patients with end-stage renal disease (ESRD) on maintenance dialysis have been rarely studied for Asian populations. We tapped Taiwan`s National Health Insurance Research Database to identify and recruit patients starting maintenance dialysis between 1999 and 2004. They were followed from initiation of dialysis until death, discontinuation of dialysis, or the end of 2008. We calculated the survival rate and mortality risk of dialysis patients with cancer. Of 40,833 dialysis patients, 2352 (5.8%) had been newly diagnosed with cancer. Being older, being male, and having chronic liver disease were factors associated with a higher risk for new cancer in ESRD dialysis patients. In men, liver cancer (20.63%) was the most frequent, followed by cancers of the bladder (16.88%) and kidney (11.61%). In women, bladder cancer (25.57%) was the most frequent, followed by cancers of the kidney (16.31%) and breast (11.20%). The 5-year survival rates for kidney and bladder cancer were higher than for other cancers; the survival rates for lung, stomach, and liver cancer were lower. In conclusion, the distribution of site-specific cancer was different between men and women in patients with ESRD on dialysis. More attention should be paid to teaching dialysis patients how to avoid the well-known cancer risks and carcinogens and individualized regular cancer screenings.

Epidemiology and outcome of acute pancreatitis in end-stage renal disease dialysis patients: a 10-year national cohort study.

BACKGROUND: The objective of this study is to determine the incidence and severity of acute pancreatitis (AP) in patients with end-stage renal disease (ESRD) on dialysis and whether the dialysis modality [hemodialysis (HD) versus peritoneal dialysis (PD)] confers a higher risk for AP as well as complications or mortality related to AP. METHODS: We analyzed national health insurance claims data of 67 078 ESRD patients initiating dialysis between 1999 and 2007 in Taiwan. All patients were followed up from the start of their dialysis to first AP diagnosis, death, end of dialysis or 31 December 2008. Cox proportional hazards models were used to identify risk factors. RESULTS: The cumulative incidence rates of AP were 0.6, 1.7, 2.6, 3.4 and 4% at 1, 3, 5, 7 and 9 years, respectively. ESRD patients on HD and PD had an AP incidence of 5.11 and 5.86 per 1000 person-years, respectively. Independent risk factors for AP in this population were being elderly, being female, having biliary stones or liver disease, and being on PD. Severe AP occurred in 44.9% of the HD patients and in 36% of the PD patients. Patients with AP on HD had a higher incidence of upper gastrointestinal (UGI) bleeding than those on PD (P = 0.002). In contrast, those with AP on PD had a higher incidence of need for total parenteral nutrition (TPN) support than those on HD (P = 0.072). Overall in-hospital mortality was 8.1%. The risk factors for mortality after an AP attack were male gender, increased age, AP severity, and the presence of diabetes mellitus or liver disease. CONCLUSIONS: ESRD patients on PD were at higher risk for AP than those on HD. HD patients with AP attacks had a greater incidence of UGI bleeding and PD patients with AP attacks a more frequent need for TPN support.

Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis.

BACKGROUND: Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF) or arteriovenous graft (AVG) creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications. RESULTS: Total 42244 patients were enrolled in this study, 37771 (89.4%) used AVF, 4473 (10.6%) used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR) 0.586, 95% confidence interval (CI) 0.557-0.616 for ACE-I use; HR 0.532, CI 0.508-0.556 for ARB use; HR 0.485, CI 0.470-0.501 for CCB use] and AVG (HR 0.557, CI 0.482-0.643 for ACE-I use, HR 0.536, CI 0.467-0.614 for ARB use, HR 0.482, CI 0.442-0.526 for CCB use). CONCLUSIONS: In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality.

Protein Kinase RNA-Like Endoplasmic Reticulum Kinase-Mediated Bcl-2 Protein Phosphorylation Contributes to Evodiamine-Induced Apoptosis of Human Renal Cell Carcinoma Cells.

We investigated the anticancer mechanism of evodiamine (EVO) against the viability of human A498 renal cell carcinoma (RCC) cells in vitro and in vivo. The in vitro study showed that EVO decreased the viability of A498 cells with the occurrence of apoptotic characteristics such as hypodiploid cells, DNA ladders, chromatin-condensed cells, and cleaved caspase (Casp)-3/poly(ADP ribose) polymerase (PARP) proteins. Pharmacological studies using chemical inhibitors of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) indicated that phosphorylation of the c-Jun N-terminal kinase (JNK) protein participated in EVO-induced cell death of A498 cells, and application of the JNK inhibitor, SP600125 (SP), inhibited EVO-induced cleavage of the Casp-3/PARP proteins and chromatin condensation according to Giemsa staining. EVO disruption of the mitochondrial membrane potential (MMP) with increased protein levels of the phosphorylated Bcl-2 protein (p-Bcl-2) was prevented by JNK inhibitors in A498 cells. A structure-activity relationship study showed that a methyl group at position 14 in EVO was important for its apoptotic effects and increased p-Bcl-2 protein in A498 cells. Furthermore, significant increases in the phosphorylated endoplasmic reticular stress protein, protein kinase RNA-like endoplasmic reticulum kinase (p-PERK at Thr980), by EVO were detected in A498 cells, and the PERK inhibitor, GSK2606414, significantly suppressed EVO-induced apoptosis, p-JNK, p-PERK, and cleaved PARP proteins. The in vivo study showed that EVO significantly reduced RCC growth elicited by a subcutaneous injection of A498 cells, and an increased protein level of p-PERK was observed according to an immunohistochemical analysis. Apoptosis by EVO was also demonstrated in other RCC cells such as 786-O, ACHN, and Caki-1 cells. This is the first study to demonstrate the anti-RCC effect of EVO via apoptosis in vitro and in vivo, and activation of JNK and PERK to induce Bcl-2 protein phosphorylation, which led to disruption of the MMP.

Evodiamine from Evodia rutaecarpa induces apoptosis via activation of JNK and PERK in human ovarian cancer cells.

BACKGROUND: Evodiamine (EVO; 8,13,13b,14-tetrahydro-14-methylindolo[2'3'-3,4]pyrido[2,1-b]quinazolin-5-[7H]-one derived from the traditional herbal medicine Evodia rutaecarpa was reported to possess anticancer activity; however, the anticancer mechanism of EVO against the viability of human ovarian cancer cells is still unclear. PURPOSE: A number of studies showed that chemotherapeutic benefits may result from targeting the endoplasmic reticular (ER) stress signaling pathway. The objective of the study is to investigate the mechanism by which ER stress protein PERK plays in EVO-induced apoptosis of human ovarian cancer cells. METHODS: Cell death analysis was performed by MTT assay, DNA fragmentation assay, and Giemsa staining. DiOC6 staining was used for mitochondrial membrane potential measurement. Protein levels were analyzed by Western blotting. Pharmacological studies using MAPK inhibitors and PERK inhibitor GSK2606414 were involved. RESULTS: The viability of human ovarian cancer cells A2780, A2780CP, ES-2, and SKOV-3 was inhibited by EVO at various concentrations in accordance with increases in the percentage of apoptotic cells, DNA ladders, and cleavage of caspase 3 and poly(ADP ribose) polymerase (PARP) proteins. Decreased viability of cells was reversed by adding caspase inhibitors VAD and DEVD in SKOV-3 and A2780CP cells, and incubation of cells with JNK inhibitor SP600125 (SP) and JNKI, but not other MAPK and AKT inhibitors including PD98059, SB203580, significantly prevented the apoptosis elicited by EVO in human ovarian cancer cells. Furthermore, increased expression of phospho-eIF2α (peIF2α) and phospho-PERK (pPERK) proteins was detected in EVO-treated human ovarian cancer cells, and that was inhibited by adding JNK inhibitors SP600125 and JNKI. Application of a PERK inhibitor GSK2606414 showed a significant protection of human ovarian cancer cells A2780 and A2780CP from EVO-induced apoptosis. EVO disruption of mitochondrial membrane potential (MMP) was also inhibited by adding JNK or PERK inhibitors. The structure-activity relationship study indicated that the alkyl group at position 14 in EVO is important for apoptosis induction via activation of JNK and PERK in human ovarian cancer cells. CONCLUSION: Evidence supporting EVO induction of apoptosis via activation of JNK and PERK to disrupt MMP in human ovarian cancer cells is provided, and the alkyl at position 14 is a critical substitution for the apoptotic actions of EVO.