PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Upregulation of SIRT1 Contributes to dmPGE2-dependent Radioprotection of Hematopoietic Stem Cells.

Exposure to potentially lethal high-dose ionizing radiation results in bone marrow suppression, known as the hematopoietic acute radiation syndrome (H-ARS), which can lead to pancytopenia and possible death from hemorrhage or infection. Medical countermeasures to protect from or mitigate the effects of radiation exposure are an ongoing medical need. We recently reported that 16,16 dimethyl prostaglandin E2 (dmPGE2) given prior to lethal irradiation protects hematopoietic stem (HSCs) and progenitor (HPCs) cells and accelerates hematopoietic recovery by attenuating mitochondrial compromise, DNA damage, apoptosis, and senescence. However, molecular mechanisms responsible for the radioprotective effects of dmPGE2 on HSCs are not well understood. In this report, we identify a crucial role for the NAD+-dependent histone deacetylase Sirtuin 1 (Sirt1) downstream of PKA and CREB in dmPGE2-dependent radioprotection of hematopoietic cells. We found that dmPGE2 increases Sirt1 expression and activity in hematopoietic cells including HSCs and pharmacologic and genetic suppression of Sirt1 attenuates the radioprotective effects of dmPGE2 on HSC and HPC function and its ability to reduce DNA damage, apoptosis, and senescence and stimulate autophagy in HSCs. DmPGE2-mediated enhancement of Sirt1 activity in irradiated mice is accompanied by epigenetic downregulation of p53 activation and inhibition of H3K9 and H4K16 acetylation at the promoters of the genes involved in DNA repair, apoptosis, and autophagy, including p53, Ku70, Ku80, LC3b, ATG7, and NF-κB. These studies expand our understanding of intracellular events that are induced by IR but prevented/attenuated by dmPGE2 and suggest that modulation of Sirt1 activity may facilitate hematopoietic recovery following hematopoietic stress. Graphical Abstract.

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway.

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

Necdin modulates leukemia-initiating cell quiescence and chemotherapy response.

Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations.

Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice.

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplantation remains limited by the inability to expand functional HSCs ex vivo. To determine the role of phosphoinositide 3-kinase (PI3K)/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human umbilical cord blood (UCB) CD34+ cells. We found that knock-down of AKT1 in human UCB CD34+ cells using short interfering RNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro. We treated human UCB CD34+ cells with an AKT-specific inhibitor (AKTi) and performed both in vitro and in vivo stem and progenitor cell assays. We found that ex vivo treatment of human HSPCs maintains CD34 expression and enhances colony formation in serial replating assays. Moreover, pharmacological inhibition of AKT enhances the short-term repopulating potential of human UCB CD34+ cells in immunodeficient mice. Mechanistically, genetic and pharmacological inhibition of AKT activity promotes human HSPC quiescence. These preclinical results suggest a positive role for AKTi during ex vivo culture of human UCB HSPCs.

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064.

Body Mass Index and the Risk of Cardiovascular and All-Cause Mortality Among Patients With Hypertension: A Population-Based Prospective Cohort Study Among Adults in Beijing, China.

BACKGROUND: Studies on the association between body mass index (BMI) and death risk among patients with hypertension are limited, and the results are inconsistent. We investigated the association between BMI and cardiovascular disease (CVD) and all-cause mortality among hypertensive patients in a population of Beijing, China. METHODS: We conducted a prospective cohort study of 2535 patients with hypertension aged 40 to 91 years from Beijing, China. Participants with a history of CVD at baseline were excluded from analysis. Cox proportional hazards regression models were used to estimate the association of different levels of BMI stratification with CVD and all-cause mortality. RESULTS: During a mean follow-up of 8.1 years, 486 deaths were identified, including 233 cases of CVD death. The multivariable-adjusted hazards ratios for all-cause mortality associated with BMI levels (<20, 20-22, 22-24, 24-26 [reference group], 26-28, 28-30, and ≥30 kg/m2) were 2.03 (95% confidence interval [CI], 1.48-2.78), 1.61 (95% CI, 1.18-2.20), 1.30 (95% CI, 0.95-1.78), 1.00 (reference), 1.12 (95% CI, 0.77-1.64), 1.33 (95% CI, 0.90-1.95), and 1.66 (95% CI, 1.10-2.49), respectively. When stratified by age, sex, or smoking status, the U-shaped association was still present in each subgroup (P > 0.05 for all interactions). Regarding the association of BMI with CVD mortality, a U-shaped trend was also observed. CONCLUSIONS: The present study showed a U-shaped association of BMI with CVD and all-cause mortality among patients with hypertension. A lowest risk of all-cause mortality was found among hypertensive patients with BMI between 24 and 26 kg/m2.

Cyanidin 3-O-ß-Glucoside Ameliorates Ethanol-Induced Acute Liver Injury by Attenuating Oxidative Stress and Apoptosis: The Role of SIRT1/FOXO1 Signaling.

BACKGROUND: The aim of this study was to examine the effects of Cyanidin 3-O-ß-glucoside (C3G) on ethanol (EtOH)-induced acute liver injury in mice as well as in cultured hepatic cells exposed to EtOH, with a focus on the involvement of Silent Mating Type Information Regulation 2 Homolog 1 (SIRT1)/Forkhead fox-O-1 (FOXO1) signaling pathway, and to explore the underlying molecular mechanisms. METHODS: C57BL/6 adolescent male mice were given EtOH via intraperitoneal injection for 2 consecutive days, and the changes in the livers were detected via hematoxylin-eosin staining. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by biochemical methods. Protein expression of SIRT1, FOXO1, acetylated FOXO1 (ac-FOXO1), GRP78, p-eukaryotic initiation factor-2 (eIF2α), and apoptosis (p-JNK, p-c-Jun, and Bax) parameters was determined by Western blot. Reactive oxygen species (ROS) was detected by flow cytometry. Human hepatocytes Chang cell line was used to assay cell apoptosis by Annexin V and propidium iodide. In addition, mRNA levels of SIRT1, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and monocyte chemoattractant protein 1 in liver tissues were detected by real-time polymerase chain reaction. RESULTS: This study demonstrated that C3G (10 mg/kg) administration diminished EtOH-induced acute liver injury compared to control group, as evidenced by the significant decreases in ALT and AST levels. Pretreatment with C3G exerted anti-inflammatory effects as indicated by the decreased TNF-α and IL-6 levels, as well as decreased inflammatory foci and ballooning cells in liver tissue. The lessened hepatic injury was associated with enhanced SIRT1 protein expression and activity by C3G in vitro and in vivo. C3G treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, p-eIF2α), which was consistent with reduced levels of both p-c-Jun and Bax. Interestingly, EX527 inhibitor did not affect the protective function of C3G on alcohol-induced cell apoptosis. Moreover, alcohol exposure increased ROS level and decreased ac-FOXO1, while C3G intervention reversed this abnormality, and this may be related to SIRT1 activity by C3G. CONCLUSIONS: Anthocyanin C3G has significant potency in antioxidant, anti-inflammatory, and anti-apoptotic effects on hepatocytes exposed to EtOH by modulating the SIRT1/FOXO1 signaling pathway. Our findings illustrate a novel and definitive therapeutic action of C3G and represent an economically feasible therapeutic intervention to treat alcoholic liver disease.

Smoking and Risk of All-cause Deaths in Younger and Older Adults: A Population-based Prospective Cohort Study Among Beijing Adults in China.

Cigarette smoking is the leading preventable cause of death worldwide. Few studies, however, have examined the modified effects of age on the association between smoking and all-cause mortality.In the current study, the authors estimated the association between smoking and age-specific mortality in adults from Beijing, China. This is a large community-based prospective cohort study comprising of 6209 Beijing adults (aged ≥40 years) studied for approximately 8 years (1991-1999). Hazard ratios (HRs) and attributable fractions associated with smoking were estimated by Cox proportional hazard models, adjusting for age, sex, alcohol intake, body mass index, systolic blood pressure, hypertension, and heart rate.The results showed, compared with nonsmokers, the multivariable-adjusted HRs for all-cause mortality were 2.7(95% confidence interval (CI):1.56-4.69) in young adult smokers (40-50 years) and 1.31 (95% CI: 1.13-1.52) in old smokers (>50 years); and the interaction term between smoking and age was significant (P = 0.026). Attributable fractions for all-cause mortality in young and old adults were 63% (95% CI: 41%-85%) and 24% (95% CI: 12%-36%), respectively. The authors estimated multivariate adjusted absolute risk (mortality) by Poisson regression and calculated risk differences and 95% CI by bootstrap estimation. Mortality differences (/10,000 person-years) were 15.99 (95% CI: 15.34-16.64) in the young and 74.61(68.57-80.65) in the old. Compared with current smokers, the HRs of all-cause deaths for former smokers in younger and older adults were 0.57 (95% CI: 0.23-1.42) and 0.96 (95% CI: 0.73-1.26), respectively.The results indicate smoking significantly increases the risks of all-cause mortality in both young and old Beijing adults from the relative and absolute risk perspectives. Smoking cessation could also reduce the excess risk of mortality caused by continuing smoking in younger adults compared with older individuals.

Sustained-release bupropion for smoking cessation in a Chinese sample: a double-blind, placebo-controlled, randomized trial.

INTRODUCTION: Bupropion is a first-line pharmacological aid for smoking cessation; however, no clinical trials have been conducted in a Chinese population. METHODS: We enrolled 248 smokers in a hospital-based, randomized, smoking cessation trial conducted at four outpatient centers in Beijing. A total of 123 participants received an 8-week course of sustained-release bupropion (Bup-SR) and 125 participants received 8 weeks of placebo. All participants received brief education and counseling on smoking cessation. We determined rates of abstinence and smoking reduction based on chemical verification and self-report at 8 and 12 weeks. RESULTS: At the end of the medication treatment (8 weeks) and at the end of the trial (12 weeks), the abstinence rates for Bup-SR were 29.3% and 39.8%, respectively, and 10.4% and 8.0% for placebo, respectively (both p < .001). Bup-SR was also superior to placebo in reducing cigarettes per day and urinary cotinine levels. CONCLUSION: Bup-SR is efficacious for smoking cessation in healthy Chinese patients treated in the outpatient setting. It is well tolerated with a few mild side effects.

[Relations between smoking, alcohol intake, physical activity, sleeping hours and the metabolic syndrome in Chinese male aged 18 - 45 years old].

OBJECTIVE: To analyze the relationship between prevalence of metabolic syndrome (MS) and behavior habits such as smoking, alcohol intake, physical activity, sleeping hours. METHODS: A multi-stage stratified cluster sampling was conducted in 31 provinces, autonomous regions, and municipalities in China according to the program of National Nutrition and Health Survey. Questionnaire survey, interview, physical examination, measurement of biochemical indices, and dietary investigation were done. In total, 4937 men aged 18 to 45 years old were selected. RESULTS: The MS prevalence was 6.9% (329/4937). The rate of drinking was 49.4% and smoking rate was 54.4%. The percentage of sleeping was hours from 7 to 8 was 70.5%. The percentage of spending time on physical activity over 420 minutes/week was as high as 41.9%. Data from single logistic regression showed volume of smoking more than 600 packs and alcohol intake were associated with high risk of MS and no significantly associations were found between MS and the duration of physical activity and the sleeping time. Multivariate logistic regression showed that the risk of MS in smokers with the volume more than 600 packs age increased significantly as compared to nonsmokers with the odds ratio as 1.443 (95%CI: 1.044 - 1.993) and 1.765 (95%CI: 1.150 - 2.708) in smokers with volume from 600 to 899 packs age, and more than 900 packs age respectively. Compared to the nondrinkers, the odds ratios were 1.525 (95%CI: 1.135 - 2.048), 2.322 (95%CI: 1.671 - 3.255) and 2.033 (95%CI: 1.478 - 2.796) in subjects volume of alcohol drinking as 1 to 2 times per week, 3 to 4 times per week and more than 5 times per week respectively. CONCLUSION: Tobacco and alcohol were associated with high risks of MS.

[Relationship between duration of low to moderate intensity physical activity and the prevalence of metabolic syndrome].

OBJECTIVE: To analyze the relationship between low to moderate physical activity and the prevalence of metabolic syndrome (MS). METHODS: A multi-stage stratified cluster sampling was conducted in 31 provinces, autonomous regions, and municipalities in the interior of China according to the program of the National Nutrition and Health Survey in 2002. Questionnaire survey, interview, physical examination, measurement of biochemical indices and dietary investigation were done. In total, the physical activity of 26 477 persons aged 18 or above were investigated. The duration of low to moderate physical activity was divided into five grades: 0-min/week, 90-min/week, 151-min/week, 301-min/week, over 420 min/week, and the MS prevalence were investigated respectively. The relationship between MS and age (including four age groups 18-, 35-, 45-, 60 or above) or the duration of physical time were investigated. RESULTS: The MS prevalence among persons aged 18 or above was 9.4% (2490/26 477). And the prevalence was 10.3% (1191/11 516) in man and 8.7%(1299/14 961) in women, respectively (χ(2) = 21.035, P = 0.000). The MS prevalence was 2.1% (127/6070) in 18-years old group and 15.0% (1012/6734) in over 60 years old group. The MS prevalence increased with increasing age (χ(2) = 776.768, P = 0.000). 81.2% (21 499/26 477) of subjects engaged in low to moderate intensity physical activity. The percentage of spending time on physical activity over 420 min/week was dominant and as high as 43.7% (11 561/26 477). The MS prevalence was 13.8% (166/1203) for 0-min grade, 13.2% (64/485) for 90-min grade, 11.8% (153/1298) for 151-min grade, 10.1% (124/1225) for 301-min grade and 12.5% (512/4090) for over 420 min grade (χ(2) = 9.58, P = 0.047). Logistic regression analysis results showed, the MS risk of subjects spending 301-min per week on low to moderate intensity physical activity was significantly low than the MS prevalence among subjects of 90-min grade, OR = 0.844 (95%CI: 0.675 - 0.968), and no statistical difference was found in people spending over 420 min per week OR = 0.936(95%CI: 0.769 - 1.136). CONCLUSION: Most of people aged 18 or above engaged in low to moderate intensity physical activity. MS prevalence may be decreased by low to moderate intensity physical activity for 301-min per week, but the decrease was not significant while the duration of time was longer than 420 min per week.

Combined effects of smoking and systolic blood pressure on risk of coronary heart disease: a cohort study in Chinese women.

OBJECTIVES: To quantify the combined effects of systolic blood pressure (SBP) and cigarette smoking on incident coronary heart disease (CHD) in women. METHODS: Overall, 86,338 women aged >or=40 years were enrolled in 1991. The follow-up evaluation was conducted in 1999-2000, with a response rate of 92.9%. RESULTS: A total of 829 CHD events (fatal and nonfatal) were observed among the participants who were free of cardiovascular diseases (CVD) at baseline. Higher SBP was significantly associated with more risk of CHD in both nonsmokers and current smokers (all p < 0.0001 for linear trends). Comparing with never smoking, both low and high levels of cigarettes smoked per day (1-7, and >or=8 cigarettes per day) and pack-years (<10, and >or=10 pack-years) were associated with increased risk of CHD in those with normal and high SBP. The multivariate adjusted relative risks (RRs) of CHD were 2.54 (95% confidence interval [CI] 2.00-3.23), 1.28 (1.01-1.63), and 1.57 (1.33-1.86) for current smokers with high SBP, current smokers with normal SBP, and nonsmokers with high SBP, respectively, compared with nonsmokers with normal SBP. The present study identified a statistically significant additive interaction between these two factors on CHD. CONCLUSIONS: Our study indicated that the combined effects of cigarette smoking and high SBP could be expected to have extra adverse effects on CHD in women, which highlights the importance of multifactorial interventions to decrease the risk of CHD, for example, quitting smoking and treatment of high blood pressure in Chinese women.

[Impact of metabolic syndrome with hyperglycemia on prevalence of stroke in Chinese].

OBJECTIVE: To investigate the impact of metabolic syndrome (MS) with or without hyperglycemia on stroke prevalence compared to that of diabetes alone. METHODS: 44 100 subjects, 20 570 males and 23 530 females, aged 25 - 75, who had participated in the Chinese Residents Nutrition and Health Examination Survey held in the mainland of China 2002, underwent anthropometry, measurement of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), high density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and 2 hour plasma glucose (2 h PG) after 75 g oral glucose tolerance test (OGTT). 22 570 subjects, 10 698 males and 11 872 females, were divided into 5 groups: control group without MS risk factors (n = 17 518), Group of diabetes mellitus (DM) without MS (n = 638), group of MS with normoglycemia (n = 2501), Group of MS with mild hyperglycemia (n = 1058), and group MS with DM (n = 855). The relationship between MS and stroke was studied by multiple logistic regression analysis. RESULTS: The prevalence of MS increased along with age. The MS prevalence rates of the subjects with FPG > or = 5.6 mmol/L in the age groups 25 - 34, 35 - 44, 45 - 54, and > or = 55 were 23.5%, 37.2%, 45.7%, and 53.0% respectively, all significantly higher than those of the subjects with the FPG < 5.6 mmol/L (2.2%, 4.7%, 7.8%, and 9.5% respectively, all P < 0.01). The prevalence rates of stroke of the groups of DM, normal blood sugar with MS, mild hyperglycemia with MS, and DM with MS were 2.94%, 2.27%, 2.89%, and 4.11%, respectively, all significantly higher than that of the control group (0.19%, all P < 0.01). After adjustment for age, sex, smoking status, and LDL-C, no significant difference was observed between the neighboring MS groups (all P > 0.05). Compared to the group of MS with normoglycemia, the OR value for stroke of the DM with MS was 1.84 (95% CI 1.20 - 2.83, P < 0.01), which was still significant after adjusting for LDL-C (P < 0.05). CONCLUSION: (1) People with glucose intolerance had very high prevalence of stroke than novmoglgcemic people. (2) Hyperglycemia in MS has an extremely important role in the impact of MS on stroke in Chinese. (3) Diabetes by itself has the same significance as the combination of MS components in the development of stroke.

[The association of stroke with high plasma low-density lipoprotein cholesterol level and metabolic syndrome in Chinese adults].

OBJECTIVE: To investigate the impact of high plasma LDL-C level with or without metabolic syndrome (MS) on the incidence of stroke in Chinese adults. METHODS: Totally 42 626 subjects (25-75 years old) from Chinese National Health and Nutrition Survey in 2002 were stratified four groups based on plasma LDL-C level:<2.00 mmol/L group, 2.00-2.50 mmol/L group, 2.51-3.31 mmol/L group, and >or=3.32 mmol/L group. The prevalence of MS (with 2005 International Diabetes Federation criteria) and stroke and the risk factors of stroke were compared among the four groups. RESULTS: (1) The prevalence of MS and stroke increased with rising of LDL-C level. The prevalence of MS in LDL-C>or=3.32 mmol/L group increased 2.5 times (7.9% vs 20.1%) as compared with that in LDL-C<2.00 mmol/L group and the prevalence of stroke increased 4.2 times (0.5% vs 2.1%), all P<0.01. (2) In subjects with similar LDL-C level, the prevalence of stroke was significantly higher in a subgroup with MS than that without (P<0.01). (3) After adjustment for age, sex and smoking, logistic regression analysis showed that both LDL-C level and MS were positively associated with the development of stroke; the odds ratio (OR) was 2.35 and 3.15 (P<0.0001), respectively. (4) Compared with the subgroup of LDL-C<2.00 mmol/L without MS, OR for stroke in the subgroups of LDL-C 2.00-2.50 mmol/L, 2.51-3.31 mmol/L, and >or=3.32 mmol/L without MS was 1.03, 1.89, and 2.08, whereas the OR for stroke in the subgroups with MS and similar level of LDL-C was 4.38, 5.23 and 6.15; this indicated that the risk of stroke in subjects with MS increased by 3-4 times compared with subjects without (P<0.0001). CONCLUSION: Both high LDL-C level and MS are independent risk factors of stroke, but the risk of stroke will be further increased in the presence of high LDL-C level plus MS. It is suggested that combined intervention therapy of LDL-C and MS will play an important role in the prevention of stroke.

[Association of stroke and different combinations of metabolic syndrome components in Chinese adults].

OBJECTIVE: To analyze the association of stroke and metabolic syndrome as well as its component combinations in Chinese adults. METHODS: Logistic regression was used to analyze the data, including anthropometric measurement, fasting plasma glucose (FPG), blood lipids, and histories of smoking, drinking, and anamnesis, of 47,414 subjects, 22,305 males and 25,105 females, aged 20-75, obtained from Chinese National Health and Nutrition Survey in 2002. RESULTS: (1) Blood pressure and waist circumference were the most important factors associated with stroke. Along with the clustering of the risk factors, the subjects became more liable to suffer from stroke. Logistic regression showed that after adjustment for age, sex, smoking status, and LDL-C level, the odd ratio (OR) values of the individuals with one, two, three, and four or more factors were 3.01 (1.89-4.81) ,4.37 (2.72-7.01), 9.20 (5.75-14.73), and 13.09 (7.98-21.49) respectively. (2) The combinations of raised hypertension plus hyperglycemia and low LDL-C and central obesity were the most hazard groups, with the OR values of 16.58 (95% CI 8.78-31.32) for stroke. The OR value for the full metabolic syndrome was 10.79 (95% CI 6.81-17.10). Hypertriglyceridemia was not an independent risk factor of stroke. (3) The relationships of metabolic risk factors and stroke were various among different age groups. Stroke was not related with blood glucose, blood pressure, serum lipids, and obesity in the subjects under 35; in those aged 35-55, diastolic Bp and low HDL-C were most significantly related to stroke; as for those above 55, systolic Bp and waist circumference were most significantly related to stroke. CONCLUSION: Central obesity cored metabolic syndrome is an important risk factor of stroke. Different combinations of the components attribute variously to stroke. In people above middle age, stroke is related to metabolic risk factors.

[Do isolated hypertension and metabolic syndrome have equal risk of stroke in Chinese adults?].

OBJECTIVE: To analyze whether isolated hypertension and metabolic syndrome ( Based on the 2005 IDF criteria) have equal risk on stroke in Chinese adults. METHODS: 25194 subjects (25-75 years old) from Chinese National Health and Nutrition Survey in 2002 were divided into control group, isolated hypertension ( i-HTN) group, metabolic syndrome (MS) without hypertension ( non-HTN/MS) group , MS with hypertension (HTN/MS) group. The clinical features and risk for stroke ( using multiple logistic stepwise regression analysis) were compared among 4 groups. RESULTS: (1) The clinic features in the i-HTN group was non-central obesity, and its plasma glucose, triglyceride 9TG), high density lipoprotein cholesterol ( HDL-C) levels were normal . (2) The prevalence of stroke in control group , i-HTN group, non-HTN/MS group and HTN/MS group was 0.14%, 1.27%, 1.19% and 2.14%, respectively. (3) After adjustment for age, sex, smoking, low density lipoprotein cholesterol level, logistic regression analysis showed that the i-HTN group, non-HTN/MS group and HTN/MS group had higher risk of stroke compared with the controls, the odd ratio (OR) were 4.18, 8.00, 8.69 (P < 0.01), respectively. Compared with i-HTN group, OR in HTN/MS group was 2.05, while no difference was found between i-HTN group and non-HTN/MS group ( P>0.05). (4) Among different components of the MS, hypertension (OR 2.33), central obesity (OR 2.09), low HDL-C (OR 1.69), hyperglycemia (OR 1.66) except hypertriglyceridemia were all significantly related to stroke (P < 0.01). CONCLUSION: (1) MS and hypertension were an independent risk factor for the development of stroke in Chinese adults. (2) Though there was no clinical features of insulin resistance in i-HTN group, it was observed that the i-HTN and non-HTN/MS had equal contribution to stroke. The risk of stroke will be further increased if hypertension included in the MS.

[Relationship between physical activity and metabolic syndrome].

OBJECTIVE: To investigate the relationship between physical activity and metabolic syndrome (MS). METHODS: A multi-stage stratified cluster sampling was conducted in 132 sampling 218,920 residents, aged 44.3 +/- 15.3 (15 - 96), in the 31 provinces, autonomous regions, and municipalities of the mainland China according to the program of the National Nutrition and Health Survey. Questionnaire survey, interview, physical examination, measurement of biochemical indices, and dietary investigation were done. Information of physical activity and measurement of fasting glucose and/or glucose 2 hours after meal, blood pressure, triglycerides, high-density lipoprotein cholesterol were obtained in 50,494 participants. Metabolic syndrome was defined according to the Chinese Medical Association's definition. The intensity of physical activity was divided into 3 categories according to the Center for Disease Control and Prevention of US/American College of Sports Medicine criteria. RESULTS: 50,495 subjects, 23,932 males (47.4%) and 26,562 females (52.6%), were diagnosed as with MS. The MS incidence of those with high intensity of physical activity was lower by 60% in comparison with those with low intensity of physical activity (odds ratio 0.60, 95% CI: 0.362 - 0.443) adjusted for age, sex, smoking, and alcohol intake. The risk of MS in those with moderate intensity of physical activity of 151 - 300 minutes/week was slightly decreased compared to those with moderate intensity of physical activity of 90 - 150 minutes/week, (odds ratio 0.935, 95% CI: 0.685 - 1.277), however, the risk of MS in those with the moderate intensity of physical activity over 300 minutes/week increased slightly (OR = 1.269, 95% CI: 0.923 - 1.745). The risk of MS in those with low-level physical activity of 301 - 420 minutes/week was lower by 35% in comparison with those with the low-level physical activity of 90 - 150 minutes/week (95% CI: 0.451 - 0.933), however, the risk of MS in those with the low-level physical activity over 420 minutes/week was 0.871, not significantly different from that of the subjects with the low-level physical activity of other intensity (odd ratio = 0.871, 95% CI: 0.643 - 1.181). The risk of MS of those with the vigorous physical activity odds rations for having MS of vigorous activity over 150 minutes/week was 0.757, lower by 25% in comparison with those with the vigorous physical activity of 10 - 60 minutes/week (95% CI: 0.603 - 0.951), adjusted for sex, age, smoking, alcohol intake and BMI. CONCLUSION: MS risk can be decreased by low level physical activity of 300 - 420 minutes/week, moderate physical activity of 90 - 300 minutes/week and vigorous physical activity of over 150 minutes/week.

[Relationship between metabolic syndrome and stroke in Chinese people].

OBJECTIVE: To explore the relationship between metabolic syndrome and stroke in Chinese people. METHODS: Data were presented for 23080 men and 25553 women aged more than 15 years old from National Nutrition and Health Survey, 2002. Metabolic syndrome definition was recommended by the CDS. RESULTS: The metabolic syndrome was significantly related with stroke( OR = 5.998,95% C14.799 - 7.496) in univariate logistic analysis, after being adjusted for age, sex, area, education, physical activity smoking and drinking, the relationship still exists between the metabolic syndrome and stroke( OR = 3.114,95 % CI ,2.432 - 3.987) . Among the component conditions, hypertension was the most leading factor associated with stroke. And individual with more components has more possibility to be affiliated with stroke (P < 0.0001). CONCLUSION: The metabolic syndrome was significantly associated with stroke in Chinese people, the metabolic syndrome and its' components should be prevented to avoid the prevalence of stroke in Chinese.