Curcumin in vitro Neuroprotective Effects Are Mediated by p62/keap-1/Nrf2 and PI3K/AKT Signaling Pathway and Autophagy Inhibition.

Oxidative stress and autophagy are potential mechanisms associated with cerebral ischemia/reperfusion injury (IRI) and is usually linked to inflammatory responses and apoptosis. Curcumin has recently been demonstrated to exhibit anti-inflammatory, anti-oxidant, anti-apoptotic and autophagy regulation properties. However, mechanism of curcumin on IRI-induced oxidative stress and autophagy remains not well understood. We evaluated the protective effects and potential mechanisms of curcumin on cerebral microvascular endothelial cells (bEnd.3) and neuronal cells (HT22) against oxygen glucose deprivation/reoxygenation (OGD/R) in vitro models that mimic in vivo cerebral IRI. The cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) activity assays revealed that curcumin attenuated the OGD/R-induced injury in a dose-specific manner. OGD/R induced elevated levels of inflammatory cytokines TNF-alpha, IL-6 as well as IL-1beta, and these effects were notably reduced by curcumin. OGD/R-mediated apoptosis was suppressed by curcumin via upregulating B-cell lymphoma-2 (Bcl-2) and downregulating Bcl-associated X (Bax), cleaved-caspase3 and TUNEL apoptosis marker. Additionally, curcumin increased superoxide dismutase (SOD) and glutathione (GSH), but suppressed malondialdehyde (MDA) and reactive oxygen species (ROS) content. Curcumin inhibited the levels of autophagic biomarkers such as LC3 II/LC3 I and Beclin1. Particularly, curcumin induced p62 accumulation and its interactions with keap1 and promoted NF-E2-related factor 2 (Nrf2) translocation to nucleus, accompanied by increased NADPH quinone dehydrogenase (Nqo1) and heme oxygenase 1 (HO-1). Treatment of curcumin increased phosphorylation-phosphatidylinositol 3 kinase (p-PI3K) and p-protein kinase B (p-AKT). The autophagy inhibitor 3-methyladenine (3-MA) activated the keap-1/Nrf2 and PI3K/AKT pathways. This study highlights the neuroprotective effects of curcumin on cerebral IRI.

Bronchovascular bundle thickening on CT as a predictor of survival and brain metastasis in patients with stage IA peripheral small cell lung cancer.

AIM: To determine if bronchovascular bundle (BVB) thickening on pretreatment computed tomography (CT) images helps predict survival in patients with peripheral small cell lung cancer (pSCLC) ≤3 cm. MATERIALS AND METHODS: The pretreatment CT examinations of 79 histopathologically proven pSCLC ≤3 cm (TNM stage I, 21; II, 13; III, 22; IV, 23) were reviewed retrospectively. The CT characteristics of the nodule and associated findings, including BVB thickening, were evaluated. Progression-free survival (PFS), overall survival (OS), and brain metastasis-free survival were compared with the presence of BVB thickening using Kaplan-Meier and Cox regression analysis. RESULTS: Among the 79 patients, 34 (43%) had BVB thickening. BVB thickening was prevalent in patients with mediastinal lymph node metastasis (50.9% versus 22.7%; p=0.024) and distant metastasis (60.9% versus 35.7%; p=0.049). Out of the 21 patients with TNM stage IA disease, the 16 patients (76.2%) without BVB thickening showed better PFS, OS, and brain metastasis-free survival (mean, 1,762 versus 483 days; p=0.019: 2,243 versus 1,328 days; p=0.038: 2,274 versus 1,287 days; p=0.038, respectively). Multivariate Cox regression analysis showed that the absence of BVB thickening (hazard ratio [HR], 7.806; 95% CI, 1.241-49.091; p=0.029) and surgery (HR, 0.075; 95% CI, 0.008-0.746; p=0.027) were independent and useful prognostic factors for PFS. CONCLUSIONS: BVB thickening was found more frequently in patients with advanced-stage pSCLC ≤3 cm, and the PFS was more favourable in patients without BVB thickening, with a similar tendency to that of OS and brain metastasis-free survival, in stage IA pSCLC.

Lateral Femoral Cutaneous Nerve Radiofrequency Ablation for Long-term Control of Refractory Meralgia Paresthetica.

BACKGROUND: Meralgia paresthetica is a term used to describe a clinical pain syndrome related to the compression or irritation of the lateral femoral cutaneous nerve (LFCN). The LFCN is a pure sensory nerve that is susceptible to compression injury. The most common compression locations are: as it courses from the lumbosacral plexus, through the abdominal cavity, under the inguinal ligament, and into the subcutaneous tissue of the thigh. METHODS: This case series is a retrospective single-center review of six patients with medically intractable meralgia paresthetica who were treated with radiofrequency ablation. To be considered for radiofrequency ablation, the patient must have been unsuccessful with medical management alone for more than two months and have a clinical diagnosis of meralgia paresthetica. Temporary relief of pain of 50% or greater was considered a positive result. Average pain scores were measured pre- and postprocedure, along with one-, two-, three-, and six-month intervals postoperation. RESULTS: All patients demonstrated immediate relief in self-reported pain scores, averaging a 75.5% reduction in pain. At the one-, two-, three-, and six-month follow-ups, patients averaged a reduction of 60.0%, 58.0%, 51.4%, and 40.5%, respectively. Both the postop and one-month follow-up pain scores were lower, statistically significantly so (P < 0.05), whereas the two-, three-, and six-month follow-ups were not statistically different from pretreatment scores. CONCLUSIONS: Although our study was small, radiofrequency ablation showed a clear reduction in average pain scores in a subset of patients who had failed standard medical therapy with a reduction in pain at one-month follow-up with relief of symptoms sometimes lasting longer than 12 months.

Public Health Efforts Can Impact Adoption of Current Susceptibility Breakpoints, but Closer Attention from Regulatory Bodies Is Needed.

Microbiological testing, including interpretation of antimicrobial susceptibility testing results using current breakpoints, is crucial for clinical care and infection control. Continued use of obsolete Enterobacteriaceae carbapenem breakpoints is common in clinical laboratories. The purposes of this study were (i) to determine why laboratories failed to update breakpoints and (ii) to provide support for breakpoint updates. The Los Angeles County Department of Public Health conducted a 1-year outreach program for 41 hospitals in Los Angeles County that had reported, in a prior survey of California laboratories, using obsolete Enterobacteriaceae carbapenem breakpoints. In-person interviews with hospital stakeholders and customized expert guidance and resources were provided to aid laboratories in updating breakpoints, including support from technical representatives from antimicrobial susceptibility testing device manufacturers. Forty-one hospitals were targeted, 7 of which had updated breakpoints since the prior survey. Of the 34 remaining hospitals, 27 (79%) assumed that their instruments applied current breakpoints, 17 (50%) were uncertain how to change breakpoints, and 10 (29%) lacked resources to perform a validation study for off-label use of the breakpoints on their systems. Only 7 hospitals (21%) were familiar with the FDA/CDC Antibiotic Resistance Isolate Bank. All hospitals launched a breakpoint update process; 16 (47%) successfully updated breakpoints, 12 (35%) received isolates from the CDC in order to validate breakpoints on their systems, and 6 (18%) were planning to update within 1 year. The public health intervention was moderately successful in identifying and overcoming barriers to updating Enterobacteriaceae carbapenem breakpoints in Los Angeles hospitals. However, the majority of targeted hospitals continued to use obsolete breakpoints despite 1 year of effort. These findings have important implications for the quality of patient care and patient safety. Other public health jurisdictions may want to utilize similar resources to bridge the patient safety gap, while manufacturers, the FDA, and others determine how best to address this growing public health issue.

Early development of de novo hepatocellular carcinoma after direct-acting agent therapy: Comparison with pegylated interferon-based therapy in chronic hepatitis C patients.

Patients with chronic hepatitis C who achieve a sustained viral response after pegylated interferon therapy have a reduced risk of hepatocellular carcinoma, but the risk after treatment with direct-acting antivirals is unclear. We compared the rates of early development of hepatocellular carcinoma after direct-acting antivirals and after pegylated interferon therapy. We retrospectively analysed 785 patients with chronic hepatitis C who had no history of hepatocellular carcinoma (211 treated with pegylated interferon, 574 with direct-acting antivirals) and were followed up for at least 24 weeks after antiviral treatment. De novo hepatocellular carcinoma developed in 6 of 574 patients receiving direct-acting antivirals and in 1 of 211 patients receiving pegylated interferon. The cumulative incidence of early hepatocellular carcinoma development did not differ between the treatment groups either for the whole cohort (1.05% vs 0.47%, P = .298) or for those patients with Child-Pugh Class A cirrhosis (3.73% vs 2.94%, P = .827). Multivariate analysis indicated that alpha-fetoprotein level >9.5 ng/mL at the time of end-of-treatment response was the only independent risk factor for early development of hepatocellular carcinoma in all patients (P < .0001, hazard ratio 176.174, 95% confidence interval 10.768-2882.473) and in patients treated with direct-acting agents (P < .0001, hazard ratio 128.402, 95% confidence interval 8.417-1958.680). In conclusion, the rate of early development of hepatocellular carcinoma did not differ between patients treated with pegylated interferon and those treated with direct-acting antivirals and was associated with the serum alpha-fetoprotein level at the time of end-of-treatment response.

A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage.

This corrects the article DOI: 10.1038/onc.2015.68.

Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells.

Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. DNA2 nuclease is an evolutionarily conserved essential enzyme in replication and HR repair. Here we demonstrate that DNA2 is overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA double strand break end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anticancer drugs by targeting druggable nuclease DNA2. We propose DNA2 inhibition as new strategy in cancer therapy by targeting replication stress, a molecular property of cancer cells that is acquired as a result of oncogene activation instead of targeting currently undruggable oncoprotein itself such as KRAS.

A novel role for non-ubiquitinated FANCD2 in response to hydroxyurea-induced DNA damage.

Fanconi anemia (FA) is a genetic disease of bone marrow failure, cancer susceptibility, and sensitivity to DNA crosslinking agents. FANCD2, the central protein of the FA pathway, is monoubiquitinated upon DNA damage, such as crosslinkers and replication blockers such as hydroxyurea (HU). Even though FA cells demonstrate unequivocal sensitivity to crosslinkers, such as mitomycin C (MMC), we find that they are largely resistant to HU, except for cells absent for expression of FANCD2. FANCD2, RAD51 and RAD18 form a complex, which is enhanced upon HU exposure. Surprisingly, although FANCD2 is required for this enhanced interaction, its monoubiquitination is not. Similarly, non-ubiquitinated FANCD2 can still support proliferation cell nuclear antigen (PCNA) monoubiquitination. RAD51, but not BRCA2, is also required for PCNA monoubiquitination in response to HU, suggesting that this function is independent of homologous recombination (HR). We further show that translesion (TLS) polymerase PolH chromatin localization is decreased in FANCD2 deficient cells, FANCD2 siRNA knockdown cells and RAD51 siRNA knockdown cells, and PolH knockdown results in HU sensitivity only. Our data suggest that FANCD2 and RAD51 have an important role in PCNA monoubiquitination and TLS in a FANCD2 monoubiquitination and HR-independent manner in response to HU. This effect is not observed with MMC treatment, suggesting a non-canonical function for the FA pathway in response to different types of DNA damage.

pH impact on reductive dechlorination of cis-dichloroethylene by Fe precipitates: an X-ray absorption spectroscopy study.

The pH impact on reductive dechlorination of cis-dichloroethylene (cis-DCE) was investigated using in situ Fe precipitates formed under iron-rich sulfate-reducing conditions. The dechlorination rate of cis-DCE increased with pH, which was attributed to changes in the solid-phase Fe concentration, the composition of Fe minerals, and the surface speciation of Fe minerals. With increasing pH, larger quantities of Fe minerals, having much greater reactivity than dissolved Fe(II), were produced. Fe-K edge X-ray absorption spectroscopy (XAS) analysis of Fe precipitates revealed the presence of multiple Fe phases with their composition varying with pH. Correlation analyses were performed to examine how the solid-phase Fe concentration, the composition of Fe minerals, and their surface speciation were linked with the cis-DCE dechlorination rate. Such analyses revealed that neither mackinawite (FeS) nor magnetite (Fe3O4) was reactive with cis-DCE dechlorination, but that Fe (oxyhydr)oxides including green rusts and Fe(OH)2 were reactive. Based on a proposed model of the surface acidity of Fe minerals, the increasing deprotonated surface Fe(II) groups with pH correlated well with the enhanced cis-DCE dechlorination.

Stimulation of the human RAD51 nucleofilament restricts HIV-1 integration in vitro and in infected cells.

Stable HIV-1 replication requires the DNA repair of the integration locus catalyzed by cellular factors. The human RAD51 (hRAD51) protein plays a major role in homologous recombination (HR) DNA repair and was previously shown to interact with HIV-1 integrase (IN) and inhibit its activity. Here we determined the molecular mechanism of inhibition of IN. Our standard in vitro integration assays performed under various conditions promoting or inhibiting hRAD51 activity demonstrated that the formation of an active hRAD51 nucleofilament is required for optimal inhibition involving an IN-DNA complex dissociation mechanism. Furthermore we show that this inhibition mechanism can be promoted in HIV-1-infected cells by chemical stimulation of the endogenous hRAD51 protein. This hRAD51 stimulation induced both an enhancement of the endogenous DNA repair process and the inhibition of the integration step. Elucidation of this molecular mechanism leading to the restriction of viral proliferation paves the way to a new concept of antiretroviral therapy based on the enhancement of endogenous hRAD51 recombination activity and highlights the functional interaction between HIV-1 IN and hRAD51.

Transplantation of mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity.

The development of effective cancer immunotherapies has been consistently hampered by several factors, including an inability to instigate long-term effective functional antitumor immunity. This is particularly true for immunotherapies that focus on the adoptive transfer of activated or genetically modified mature CD8+ T cells. In this study, we sought to alter and enhance long-term host immunity by genetically modifying, then transplanting, mouse HSCs. We first cloned a previously identified tumor-reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen tyrosinase-related protein 1 (Tyrp1), then constructed both a high-expression lentivirus vector and a TCR-transgenic mouse expressing the genes encoding this TCR. Using these tools, we demonstrated that both mouse and human HSCs established durable, high-efficiency TCR gene transfer following long-term transplantation into lethally irradiated mice transgenic for HLA-DR4. Recipients of genetically modified mouse HSCs developed spontaneous autoimmune vitiligo that was associated with the presence of a Th1-polarized memory effector CD4+ T cell population that expressed the Tyrp1-specific TCR. Most importantly, large numbers of CD4+ T cells expressing the Tyrp1-specific TCR were detected in secondary HLA-DR4-transgenic transplant recipients, and these mice were able to destroy subcutaneously administered melanoma cells without the aid of vaccination, immune modulation, or cytokine administration. These results demonstrate the creation of what we believe to be a novel translational model of durable lentiviral gene transfer that results in long-term effective immunity.

Synthesis of proline-derived dipeptides and their catalytic enantioselective direct aldol reactions: catalyst, solvent, additive and temperature effects.

A series of dipeptides of L-proline-L-amino acid and L-proline-D-amino acid were synthesized to evaluate the catalytic effect for asymmetric direct aldol reactions. In the direct aldol reaction, a catalyst of L-proline-L-amino acid achieves better enantioselectivity than the corresponding L-proline-D-amino acid catalyst. Solubility of the dipeptide catalysts in the solvents is a key point for achieving a better yield of the direct aldol reaction, while hydrogen bonding of solvent does not play an important role in attaining better enantioselectivity and yield. Yield and enantioselectivity of the direct aldol reaction in water were improved by NMM and SDS additives, but the results that were done in plain DMSO were even better.

Changes of aqueous vascular endothelial growth factor and pigment epithelium-derived factor following intravitreal bevacizumab for macular oedema secondary to branch retinal vein occlusion.

BACKGROUND: To investigate sequential changes of aqueous vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in macular oedema secondary to branch retinal vein occlusion (BRVO) following intravitreal injection of bevacizumab (IVB). METHODS: We recruited 10 healthy controls and 40 patients with BRVO. Aqueous levels of VEGF and PEDF were measured by ELISA at the time of IVB and 6 weeks later. Non-response to IVB was defined as showing persistent macular oedema based on reduction of central macular thickness by less than 20% from baseline measurements by optical coherence tomography and vision improvement by <0.3 log MAR at 6 weeks after IVB. Fluorescein angiography was performed after resolution of foveal haemorrhage. We compared aqueous levels of VEGF and PEDF between responders and non-responders. RESULTS: The aqueous levels of VEGF and PEDF were significantly higher in 16 non-responders than in 24 responders at baseline measurements (491 +/- 231 pg/mL vs. 250 +/- 112 pg/mL, P < 0.001; 32 +/- 4 ng/mL vs. 25 +/- 5 ng/mL, P < 0.001, respectively). Six weeks after IVB, the aqueous levels of VEGF and PEDF were still higher in non-responders than in responders (388 +/- 141 pg/mL vs. 104 +/- 40 pg/mL, P < 0.001; 30 +/- 8 ng/mL vs. 18 +/- 5 ng/mL, P < 0.001, respectively). Fluorescein angiography revealed that non-responders showed higher frequencies of macular ischaemia and ischaemic BRVO. CONCLUSIONS: Our results indicate that aqueous VEGF levels are associated with persistent macular oedema secondary to ischaemic BRVO following IVB.

High-avidity autoreactive CD4+ T cells induce host CTL, overcome T(regs) and mediate tumor destruction.

Despite progress made over the past 25 years, existing immunotherapies have limited clinical effectiveness in patients with cancer. Immune tolerance consistently blunts the generated immune response, and the largely solitary focus on CD8+ T cell immunity has proven ineffective in the absence of CD4+ T cell help. To address these twin-tier deficiencies, we developed a translational model of melanoma immunotherapy focused on the exploitation of high-avidity CD4+ T cells that become generated in germline antigen-deficient mice. We had previously identified a tyrosinase-related protein-1 specific HLA-DRB1*0401-restricted epitope. Using this epitope in conjunction with a newly described tyrosinase-related protein-1 germline-knockout, we demonstrate that endogenous tyrosinase-related protein-1 expression alters the functionality of the autoreactive T cell repertoire. More importantly, we show, by using major histocompatibility complex-mismatched combinations, that CD4+ T cells derived from the self-antigen deficient host indirectly triggers the eradication of established B16 lung metastases. We demonstrate that the treatment effect is mediated entirely by endogenous CD8+ T cells and is not affected by the depletion of host regulatory T cells. These findings suggest that high-avidity CD4+ T cells can overcome endogenous conditions and mediate their antitumor effects exclusively through the elicitation of CD8+ T cell immunity.

Improving neural network prediction of effluent from biological wastewater treatment plant of industrial park using fuzzy learning approach.

Three types of adaptive network-based fuzzy inference system (ANFIS) in which the online monitoring parameters served as the input variable were employed to predict suspended solids (SS(eff)), chemical oxygen demand (COD(eff)), and pH(eff) in the effluent from a biological wastewater treatment plant in industrial park. Artificial neural network (ANN) was also used for comparison. The results indicated that ANFIS statistically outperforms ANN in terms of effluent prediction. When predicting, the minimum mean absolute percentage errors of 2.90, 2.54 and 0.36% for SS(eff), COD(eff) and pH(eff) could be achieved using ANFIS. The maximum values of correlation coefficient for SS(eff), COD(eff), and pH(eff) were 0.97, 0.95, and 0.98, respectively. The minimum mean square errors of 0.21, 1.41 and 0.00, and the minimum root mean square errors of 0.46, 1.19 and 0.04 for SS(eff), COD(eff), and pH(eff) could also be achieved.

Cripto-1 overexpression is involved in the tumorigenesis of gastric-type and pancreatobiliary-type intraductal papillary mucinous neoplasms of the pancreas.

Human Cripto-1, a membrane-bound protein, plays an important role during early embryogenesis and has oncogenic properties, including cell transformation and enhancement of invasion. Cripto-1 is up-regulated in various malignant tissues and premalignant lesions. However, Cripto-1 expression in intraductal papillary mucinous neoplasms (IPMNs) has yet to be reported. This study aimed to investigate Cripto-1 expression in IPMNs and evaluate the expression patterns according to the histological grade or phenotypic subclassification. Cripto-1 expression was evaluated by immunohistochemistry using 37 IPMN tissue samples and real-time RT-PCR analysis of seven frozen samples. Cripto-1 was up-regulated in 59.5% of IPMNs. Cripto-1 was positively stained in 3 of 4 (75%) adenomas, 12 of 19 (63.2%) borderline neoplasms, 5 of 11 (45.5%) non-invasive carcinomas and 2 of 3 (66.7%) invasive carcinomas. There was no correlation between Cripto-1 overexpression and the histological grade (P>0.05). Cripto-1 expression was significantly increased in pancreatobiliary- (4/5, 80%) and gastric-type (13/19, 68.4.2%) IPMNs compared with those of the intestinal type (2/10, 20%; P<0.01). Cripto-1 mRNA expression was higher in gastric- and pancreatobiliary-type IPMNs than in intestinal ones, supporting the immunohistochemical results. It is concluded that Cripto-1 overexpression is involved in the tumorigenesis of gastric- and pancreatobiliary-type IPMNs.

Whole-body positron emission tomography with 18F-fluorodeoxyglucose is an effective method to detect extra-pelvic recurrence in uterine sarcomas.

PURPOSE OF INVESTIGATION: To assess the clinical use of F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in the post-therapy surveillance of uterine sarcoma. METHODS: Eight whole-body FDG-PET studies were performed in seven women with previously treated uterine sarcoma. Conventional image studies (computed tomography) and physical examinations were performed for follow-up. All FDG-PET studies were indicated to localize suspected recurrences noted by conventional methods. RESULTS: The per case sensitivity of the FDG-PET studies and CT scans was 85.7% (6/7) and 100% (7/7), respectively (p = 0.174). FDG-PET was able to detect seven extrapelvic metastastic sites below the diaphragm (7/7, sensitivity: 100%), including the liver, spleen, paraaortic lymph node, spine and paracolic gutter, as well as pulmonary lesions in five patients, while the CT scan detected only three lesions (3/7, sensitivity: 42.9%; p = 0.070). FDG-PET detected only four recurrent pelvic lesions (4/6) and CT scan detected six (6/6) recurrent pelvic lesions (66.7% vs 100%, p = 0.455). CONCLUSIONS: The FDG-PET showed a better detection rate than the abdominal CT scan for extrapelvic metastatic lesions and a similar detection rate as well as abdominal CT scan. FDG-PET can serve as a useful detection tool for patients with uterine sarcomas because nearly 80% of recurrence involve an extrapelvic site.

The metabolic syndrome increases cardiovascular mortality in Taiwanese elderly.

BACKGROUND: The prevalence of the metabolic syndrome (MetS) is high among the elderly. However, evidence that mortality increases with MetS is rare. In this study, we investigated the relationship between MetS, cardiovascular disease (CVD) and all cause mortality in the elderly. MATERIALS AND METHODS: A total 10 547 participants, aged 65 years and older, of baseline cohort were recruited from four nationwide Health Screening Centres in Taiwan from 1998 to 1999. The metabolic syndrome was defined according to the America Heart Association/National Heart Lung Blood Institute definition. Cox proportional hazards regression analyses were used to estimate the relative risks (RRs) of CVD and all cause mortality for those with MetS for up to 8 years of follow-up. RESULTS: The baseline prevalence of MetS was 50.1% (45.6% in men and 54.4% in women, respectively). A total of 1312 participants died; of these, 300 participants died from CVD. Adjusted for age, gender, smoking, total cholesterol and estimated glomerular filtration rate, the RRs for CVD and all cause mortality among participants with MetS were 1.48 (95% confidence interval = 1.16-1.90) and 1.16 (1.03-1.30), respectively, for participants compared to those without MetS. The mean RRs for CVD, however, ranged from 1.21 to 5.31 among different combinations of MetS components. CONCLUSION: The elderly with MetS, compared to those without MetS, had a higher CVD and all cause mortality in Taiwan. Furthermore, different combinations of MetS components posed different risks to the mortality, which deserves further research in the future.