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ABSTRACT: We aimed to improve the diagnostic accuracy of automatic myocardial perfusion SPECT (MPS) interpretation analysis for the prediction of coronary artery disease (CAD) by integrating several quantitative perfusion and functional variables for noncorrected (NC) data by Support Vector Machine (SVM) algorithm, a computer method for machine learning. METHODS: Rest-stress gated 99mTc MPS NC studies (n = 957) from 623 consecutive patients with correlating invasive coronary angiography and 334 with a low likelihood of CAD (<5%) were assessed. Stenosis ≥50% in left main or ≥70% in all other vessels was considered abnormal. Total perfusion deficit (TPD) was computed automatically. In addition, ischemic changes (ISCHs) and ejection fraction changes (EFCs) between stress and rest were derived by quantitative software. The SVM was trained using a group of 125 patients (25 with low-likelihood, 25 with 0-vessel, 25 with 1-vessel, 25 with 2-vessel, and 25 with 3-vessel CAD) with the above quantitative variables and second-order polynomial fitting. The remaining patients (n = 832) were categorized using probability estimates, with CAD defined as a probability estimate ≥ 0.50. The diagnostic accuracy of SVM was also compared with visual segmental scoring by 2 experienced readers. RESULTS: The sensitivity of SVM (84%) was significantly better than ISCH (75%, P < 0.05) and EFC (31%, P < 0.05). The specificity of SVM (88%) was significantly better than TPD (78%, P < 0.05) and EFC (77%, P < 0.05). The diagnostic accuracy of SVM (86%) was significantly better than TPD (81%), ISCH (81%), or EFC (46%) (P < 0.05 for all). The receiver-operating-characteristic (ROC) area under the curve for SVM (0.92) was significantly better than TPD (0.90), ISCH (0.87), and EFC (0.64) (P < 0.001 for all). The diagnostic accuracy of SVM was comparable to the overall accuracy of both visual readers (85% vs. 84%, P = NS). The ROC area under the curve for SVM (0.92) was significantly better than that of both visual readers (0.87 and 0.88, P < 0.03). CONCLUSION: Computational integration of quantitative perfusion and functional variables using the SVM approach significantly improves the diagnostic accuracy of MPS and can significantly outperform visual assessment based on ROC analysis.
Journal of Nuclear Medicine 03/2013; · 6.38 Impact Factor
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ABSTRACT: Both arsenite and benzo(a)pyrene (BaP) are known human carcinogens. Studies on the mode-of-action of arsenite indicate that it can also act as co-carcinogen or as a cancer promoter, and that it can facilitate progression of cancers. Some studies on development of lung cancers have suggested a synergism between arsenite exposure and cigarette smoking. The mechanism of action for such an effect, however, remains obscure. In the present study, we investigated the effects of HIF-2α on arsenite- and BaP-induced cell malignant transformation as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. The results show that arsenite accelerates the neoplastic transformation and migration of cells and enhances chromosomal aberrations induced by BaP. HIF-2α is involved in blocking the effects of arsenite in activating the ATM/Chk-2 pathway and in repair of DNA damage induced by BaP. Moreover, blocking of HIF-2α prevents the effects of arsenite on the neoplastic transformation, cell migration, and chromosomal aberrations caused by BaP. These results indicate that the repressive effect of HIF-2α on the ATM/Chk-2 pathway leads to genomic instability, which is involved in arsenite-accelerated, BaP-induced malignant transformation of HBE cells.
Toxicology Letters 01/2013; · 3.23 Impact Factor
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ABSTRACT: High-sensitivity dedicated cardiac camera systems provide an opportunity to lower the injected doses for SPECT myocardial perfusion imaging (MPI), but the exact limits for lowering doses have not been determined. List-mode data acquisition allows for reconstruction of various fractions of acquired counts, enabling a simulation of gradually lower administered dose. We aimed to determine the feasibility of very low dose MPI by exploring the minimal count level in the myocardium required for accurate MPI. METHODS: Seventy-nine patients were studied (mean body mass index, 30.0 ± 6.6; range, 20.2-54.0 kg/m(2)) who underwent 1-d standard-dose (99m)Tc-sestamibi exercise or adenosine rest-stress MPI for clinical indications using a cadmium-zinc-telluride dedicated cardiac camera. The imaging time was 14 min, with averaged 803 ± 200 MBq (21.7 ± 5.4 mCi) of (99m)Tc injected at stress. To simulate clinical scans with a lower dose at that imaging time we reframed the list-mode raw data. Accordingly, 6 stress-equivalent datasets were reconstructed containing various count fractions of the original scan. Automated quantitative perfusion and gated SPECT software was used to quantify total perfusion deficit (TPD) and ejection fraction for all 553 datasets (7 × 79). The minimal acceptable left ventricular region counts were determined on the basis of a previous report with repeatability of same-day, same-injection Anger camera studies. Pearson correlation coefficients and the SD of differences in TPD for all scans were calculated. RESULTS: The correlations of quantitative perfusion and function analysis were excellent for both global and regional analysis between original scans and all simulated low-count scans (all r ≥ 0.95, P < 0.0001). The minimal acceptable counts were determined to be 1.0 million for the left ventricular region. At this count level, the SD of differences was 1.7% for TPD and 4.2% for ejection fraction. This count level would correspond to a 92.5-MBq (2.5-mCi) injected dose for the 14-min acquisition or 125.8-MBq (3.4-mCi) injected dose for the 10-min acquisition. CONCLUSION: 1.0 million counts appear to be sufficient to produce myocardial images that agree well with 8.0-million-count images on quantitative perfusion and function parameters. With a dedicated cardiac camera, these images can be obtained over 10 min with an effective radiation dose of less than 1 mSv without significant sacrifice of accuracy.
Journal of Nuclear Medicine 01/2013; · 6.38 Impact Factor
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ABSTRACT: We compared the performance of fully automated quantification of attenuation-corrected (AC) and noncorrected (NC) myocardial perfusion SPECT (MPS) with the corresponding performance of experienced readers for detection of coronary artery disease (CAD). METHODS: Rest-stress (99m)Tc-sestamibi MPS studies (n = 995; 650 consecutive cases with coronary angiography and 345 with likelihood of CAD < 5%) were obtained by MPS with AC. The total perfusion deficit (TPD) for AC and NC data was compared with the visual summed stress and rest scores of 2 experienced readers. Visual reads were performed in 4 consecutive steps with the following information progressively revealed: NC data, AC + NC data, computer results, and all clinical information. RESULTS: The diagnostic accuracy of TPD for detection of CAD was similar to both readers (NC: 82% vs. 84%; AC: 86% vs. 85%-87%; P = not significant) with the exception of the second reader when clinical information was used (89%, P < 0.05). The receiver-operating-characteristic area under the curve (ROC AUC) for TPD was significantly better than visual reads for NC (0.91 vs. 0.87 and 0.89, P < 0.01) and AC (0.92 vs. 0.90, P < 0.01), and it was comparable to visual reads incorporating all clinical information. The per-vessel accuracy of TPD was superior to one reader for NC (81% vs. 77%, P < 0.05) and AC (83% vs. 78%, P < 0.05) and equivalent to the second reader (NC, 79%; and AC, 81%). The per-vessel ROC AUC for NC (0.83) and AC (0.84) for TPD was better than that for the first reader (0.78-0.80, P < 0.01) and comparable to that of the second reader (0.82-0.84, P = not significant) for all steps. CONCLUSION: For detection of ≥70% stenoses based on angiographic criteria, a fully automated computer analysis of NC and AC MPS data is equivalent for per-patient and can be superior for per-vessel analysis, when compared with expert analysis.
Journal of Nuclear Medicine 01/2013; · 6.38 Impact Factor
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Gang Chen, Yuan Xu,
Yinghua Lin,
Xiaolan Lai,
Jin Yao,
Baoying Huang,
Zichun Chen,
Huibin Huang,
Xianguo Fu,
Lixiang Lin,
Shenghan Lai,
Junping Wen
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ABSTRACT: BACKGROUND: Genetic determinations are important in type 2 diabetes (T2D) pathology. We investigated associations between genetic variants of 17 diabetes-related genes/loci, T2D and diabetic complications in Chinese She subjects. METHODS: A comprehensive gene-based association study was conducted using 17 single nucleotide polymorphisms (SNPs) in Chinese She subjects with normal glucose tolerance (NGT; n=1119), impaired glucose regulation (IGR; n=1767), and T2D (n=443). We applied major abnormal Minnesota Code findings to predict cardiovascular risk and estimated glomerular filtration rate (eGFR) to assess kidney function. RESULTS: Nine variants in FTO rs8050136, WFS1 rs10010131, CDKN2A/B rs10811661, KCNJ11 rs5219, CDC123/CAMK1D rs12779790, JAZF1 rs864745, SLC30A8 rs13266634, CDKAL1 rs10946398 and HHEX/IDE rs5015480 were significantly associated with T2D (p<0.05). SNPs in WFS1 rs10010131, CDKN2A/B rs10811661, CDC123/CAMK1D rs12779790, JAZF1 rs864745, FTO rs8050136 and HHEX/IDE rs5015480 were associated with T2D and IGR. Risk alleles in WFS1 rs10010131, IGF2BP2 rs4402960, CDKAL1 rs10946398, FTO rs8050136, KCNQ1 rs2237897 and ADAMTS9 rs4607103 were significantly associated with decreased HOMA-β (p<0.05). After adjusting for age, gender and BMI, genetic variants JAZF1 rs864745, FTO rs8050136, and HHEX/IDE rs5015480 were significantly related to reduced eGFR (p<0.05). Genetic variants in WFS1 rs10010131, CDKN2A/B rs10811661, CDC123/CAMID rs12779790, JAZF1 rs864745, FTO rs80501360, CDKAL1 rs10946398 and HHEX/IDE rs5015480 correlated with abnormal major Minnesota Code findings (p<0.05). CONCLUSION: Variants in WFS1, CDKN2A/B, KCNJ11, CDC123/CAMK1D, JAZF1, SLC30A8, FTO, CDKAL1 and HHEX/IDE genes are significantly associated with T2D in She Chinese subjects. JAZF1, FTO, CDKAL1 and HHEX/IDE are associated with diabetic nephropathy. WFS1, CDKN2A/B, CDC123/CAMK1D, JAZF1, FTO, CDKAL1 and HHEX/IDE are associated with cardiovascular risk. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.
Journal of Diabetes 01/2013;
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Lu Shen,
Min Ling,
Yuan Li, Yuan Xu,
Yun Zhou,
Jing Ye,
Ying Pang,
Yue Zhao,
Rongrong Jiang,
Jianping Zhang,
Qizhan Liu
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ABSTRACT: To establish the functions of miR-21 and the roles of two feedback regulation loops, miR-21-Spry1-ERK/NF-κB and miR-21-Pdcd4-JNK/c-Jun, in arsenite-transformed human embryo lung fibroblast (HELF) cells.
For arsenite-transformed HELF cells, apoptosis, clonogenicity, and capacity for migration were determined by Hoechst staining, assessment of their capacity for anchorage-independent growth, and wound-healing, respectively, after blockage, with inhibitors or with siRNAs, of signal pathways for JNK/c-Jun or ERK/NF-κB. Decreases of miR-21 levels were determined with anti-miR-21, and the up-regulation of Pdcd4 and Spry1 was assessed in transfected cells; these cells were molecularly characterized by RT-PCR, qRT-PCR, Western blots, and immunofluorescence assays.
MiR-21 was highly expressed in arsenite-transformed HELF cells and normal HELF cells acutely treated with arsenite, an effect that was concomitant with activation of JNK/c-Jun and ERK/NF-κB and down-regulation of Pdcd4 and Spry1 protein levels. However, there were no significant changes in mRNA levels for Pdcd4 and Spry1, which suggested that miR-21 regulates the expressions of Pdcd4 and Spry1 through translational repression. In arsenite-transformed HELF cells, blockages of JNK/c-Jun or ERK/NF-κB with inhibitors or with siRNAs prevented the increases of miR-21and the decreases of the protein levels but not the mRNA levels of Pdcd4 and Spry1. Down-regulation of miR-21 and up-regulations of Pdcd44 or Spry1 blocked the arsenite-induced activations of JNK/c-Jun or ERK/NF-κB, indicating that knockdown of miR-21 inhibits feedback of ERK activation and JNK activation via increases of Pdcd4 and Spry1 protein levels, respectively. Moreover, in arsenite-transformed HELF cells, inhibition of miR-21 promoted cell apoptosis, inhibited clonogenicity, and reduced migration.
The results indicate that miR-21 is both a target and a regulator of ERK/NF-κB and JNK/c-Jun and the feedback regulations of miR-21 and MAPKs via Pdcd4 and Spry1, respectively, are involved in arsenite-induced malignant transformation of HELF cells.
PLoS ONE 01/2013; 8(3):e57652. · 4.09 Impact Factor
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ABSTRACT: The biphasic effects of arsenite, in which low levels of arsenite induce cell proliferation and high levels of arsenite induce DNA damage and apoptosis, apparently contribute to arsenite-induced carcinogenesis. However, the mechanisms underlying this phenomenon are not well understood. In this study, we investigated the effects of different levels of arsenite on cell proliferation, DNA damage and apoptosis as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. Our results show that a low level of arsenite activates extracellular signal-regulated kinases (ERK), which probably mediate arsenite-inhibited degradation of ubiquitinated hypoxia-inducible factor-2α (HIF-2α) in HBE cells. ERK inhibition blocks cell proliferation induced by a low level of arsenite, in part via HIF-2α. In contrast, a high level of arsenite activates c-Jun N-terminal kinases (JNK), which provoke a response to suppress ubiquitinated HIF-1α degradation. Down-regulation of HIF-1α by inhibiting JNK, however, increases the DNA damage but decreases the apoptosis induced by a high level of arsenite. Thus, data in the present study suggest that the accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in different levels of arsenite-induced biphasic effects, with low levels of arsenite inducing cell proliferation and high levels of arsenite inducing DNA damage and apoptosis in HBE cells.
Toxicology and Applied Pharmacology 11/2012; · 4.45 Impact Factor
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Rongrong Jiang,
Yuan Li, Yuan Xu,
Yun Zhou,
Ying Pang,
Lu Shen,
Yue Zhao,
Jianping Zhang,
Jianwei Zhou,
Xinru Wang,
Qizhan Liu
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ABSTRACT: Exposure of humans to inorganic arsenic can cause skin cancer. The epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like properties are essential steps in the initiation of human skin cancers; however, the mechanisms of action remain obscure. We have found that, during the neoplastic transformation induced by a low concentration (1.0 μM) of arsenite in human keratinocyte HaCaT cells, the cells undergo an EMT and then acquire a malignant CSC-like phenotype. With longer times for transformation of HaCaT cells, there were increased activations of IκB kinase β (IKKβ), inhibitor nuclear factor-kappa B alpha (IκBα), and nuclear factor κB (NF-κB) RelA and increases in the level of Snail. Further, during the transformation of HaCaT cells, the activation of NF-κB RelA up-regulated Snail levels. Inhibition of NF-κB RelA blocked the arsenite-induced EMT, acquisition of a CSC-like phenotype, and neoplastic transformation. These observations show that EMT, along with acquisition of a CSC-like phenotype mediated by IKKβ/IκBα/RelA signal pathway via Snail, contributes to a low concentration of arsenite-induced tumorigenesis.
Archive für Toxikologie 10/2012; · 4.67 Impact Factor
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Yuan Li,
Rongrong Jiang,
Yue Zhao, Yuan Xu,
Min Ling,
Ying Pang,
Lu Shen,
Yun Zhou,
Jianping Zhang,
Jianwei Zhou,
Xinru Wang,
Qizhan Liu
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ABSTRACT: Biphasic dose-response relationship induced by environmental agents is often characterized with the effect of low-dose stimulation and high dose inhibition. Some studies showed that arsenite may induce cell proliferation and apoptosis via biphasic dose-response relationship in human cells; however, mechanisms underlying this phenomenon are not well understood. Our present study shows that, for human keratinocytes (HaCaT) cells, a low concentration of arsenite activates extracellular signal-regulated kinases (ERKs), which leads to up-regulation of nuclear factor κB (NF-κB) binding to DNA and to elevated, NF-κB-dependent expression of mot-2 (a p53 inhibitor) and survivin (an inhibitor of apoptosis). Activation of p53 is blocked, and neoplastic transformation is enhanced. Inhibition of ERKs reduces cell proliferation and neoplastic transformation. In contrast, a high concentration of arsenite activates c-Jun N-terminal kinases (JNKs), positive regulators of p53, by binding to p53 and preventing its murine double minute 2 (mdm2)-mediated degradation. The elevated levels of p53 lead to repair of DNA damage and apoptosis. Inhibition of JNKs increases DNA damage but decreases apoptosis. By identifying a mechanism whereby ERKs and JNKs-mediated regulation of the p53-survivin signal pathway is involved in the biphasic effects of arsenite on human keratinocytes, our data expand understanding of arsenite-induced cell proliferation, neoplastic transformation, DNA damage, and apoptosis.
Toxicology 06/2012; 300(3):121-31. · 3.68 Impact Factor
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ABSTRACT: Hypoxia-inducible factors (HIFs), which consist of α and β subunits, are transcription factors involved in regulation of a variety of cellular functions. By blocking the function of the tumor suppressor p53, over-expressions of HIFs are linked to carcinogenesis and tumor progression. Inorganic arsenic, a ubiquitous environmental contaminant, is associated with an increased risk of cancer. Although there are several hypotheses regarding arsenic-induced carcinogenesis, the mechanism of action remains obscure. We have shown that long-term exposure of human bronchial epithelial (HBE) cells to a low level of arsenite increases their proliferation rate and anchorage-independent growth. When introduced into nude mice, the transformed cells are tumorigenic. The present report demonstrates that, with increased time of exposure to arsenite, there is more increased expression of HIF-2α, but not HIF-1α. These factors are known to have different functions, and, in some cases, opposite effects. Arsenite induces accumulation of HIF-2α by inhibiting its degradation through the ubiquitin-mediated proteasome pathway. HIF-2α knockdown, but not HIF-1α knockdown, increases the activation of p53. Finally, inhibition of HIF-2α blocks arsenite-induced proliferation and malignant transformation. Thus, our studies show that blockade of p53 function by inhibiting the ubiquitin-mediated proteasome degradation of HIF-2α, but not that of HIF-1α, is involved in arsenite-induced proliferation and neoplastic transformation of HBE cells.
Archive für Toxikologie 03/2012; 86(6):947-59. · 4.67 Impact Factor
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Yuan Xu,
Pui Y Lee,
Yi Li,
Chao Liu,
Haoyang Zhuang,
Shuhong Han,
Dina C Nacionales,
Jason Weinstein,
Clayton E Mathews,
Lyle L Moldawer,
Shi-Wu Li,
Minoru Satoh,
Li-Jun Yang,
Westley H Reeves
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ABSTRACT: Genetic polymorphisms of IFN regulatory factor 5 (IRF5) are associated with an increased risk of lupus in humans. In this study, we examined the role of IRF5 in the pathogenesis of pristane-induced lupus in mice. The pathological response to pristane in IRF5(-/-) mice shared many features with type I IFN receptor (IFNAR)(-/-) and TLR7(-/-) mice: production of anti-Sm/RNP autoantibodies, glomerulonephritis, generation of Ly6C(hi) monocytes, and IFN-I production all were greatly attenuated. Lymphocyte activation following pristane injection was greatly diminished in IRF5(-/-) mice, and Th cell differentiation was deviated from Th1 in wild-type mice toward Th2 in IRF5(-/-) mice. Th cell development was skewed similarly in TLR7(-/-) or IFNAR(-/-) mice, suggesting that IRF5 alters T cell activation and differentiation by affecting cytokine production. Indeed, production of IFN-I, IL-12, and IL-23 in response to pristane was markedly decreased, whereas IL-4 increased. Unexpectedly, plasmacytoid dendritic cells (pDC) were not recruited to the site of inflammation in IRF5(-/-) or MyD88(-/-) mice, but were recruited normally in IFNAR(-/-) and TLR7(-/-) mice. In striking contrast to wild-type mice, pristane did not stimulate local expression of CCL19 and CCL21 in IRF5(-/-) mice, suggesting that IRF5 regulates chemokine-mediated pDC migration independently of its effects on IFN-I. Collectively, these data indicate that altered production of IFN-I and other cytokines in IRF5(-/-) mice prevents pristane from inducing lupus pathology by broadly affecting T and B lymphocyte activation/differentiation. Additionally, we uncovered a new, IFN-I-independent role of IRF5 in regulating chemokines involved in the homing of pDCs and certain lymphocyte subsets.
The Journal of Immunology 03/2012; 188(8):4113-21. · 5.79 Impact Factor
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ABSTRACT: This study investigated the impact of family history of diabetes (FHD) on β-cell function among Chinese with normal glucose tolerance.
A multistage, stratified, cluster random sampling method was used to select a provincially representative sample from Fujian Province. Eventually, a total of 1,183 subjects were entered into the analysis. Several indexes were used to assess the function of β cells, including homeostasis model assessment (HOMA) of insulin resistance (IR), HOMA of β cells, insulinogenic index (IGI), and disposition index.
Overweight, increased body mass index, higher low-density lipoprotein cholesterol, and higher total cholesterol (TC) were the dominant features of positive FHD (FHD(+)). The FHD(+) subjects had lower insulin sensitivity (P<0.05). FHD(+) subjects showed higher risk of IR after adjusting for other risk factors (odds ratio 1.523 [1.272-2.009]). However, there was no significant difference in insulin secretion between the two groups. With the use of the multiple linear regression model, waist circumference (WC) and triglycerides (TGs) were found to be independent risk factors of the decline of insulin sensitivity in FHD(+) subjects, and insulin sensitivity declined significantly (P<0.05) with the increase of WC and TGs. In addition, the offspring of fathers with diabetes (PT2D) were much older and had higher TC than those of mothers with diabetes (MT2D). After adjusting for gender of the parents, there was no difference between MT2D and PT2D on insulin sensitivity.
Inheritance if diabetes is associated with the decline of insulin sensitivity. In addition, insulin sensitivity declined with increasing WC and TG in FHD(+) subjects.
Diabetes Technology & Therapeutics 03/2012; 14(6):463-8. · 1.93 Impact Factor
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ABSTRACT: Transient ischemic dilation (TID) of the left ventricle in myocardial perfusion SPECT (MPS) has been shown to be a clinically useful marker of severe coronary artery disease (CAD). However, TID has not been evaluated for 99mTc-sestamibi rest/stress protocols (Mibi-Mibi). We aimed to develop normal limits and evaluate diagnostic power of TID ratio for Mibi-Mibi scans.
TID ratios were automatically derived from static rest/stress MPS (TID) and gated rest/stress MPS from the end-diastolic phase (TID(ed)) in 547 patients who underwent Mibi-Mibi scans [215 patients with correlating coronary angiography and 332 patients with low likelihood (LLk) of CAD]. Scans were classified as severe (≥ 70% stenosis in proximal left anterior descending (pLAD) artery or left main (LM), or ≥ 90% in ≥ 2 vessels), mild to moderate (≥ 90% stenosis in 1 vessel or ≥ 70%-90% in ≥ 1 vessel except pLAD or LM), and normal (<70% stenosis or LLk group). Another classification based on the angiographic Duke prognostic CAD index (DI) was also applied: DI ≥ 50, 30 ≤ DI < 50 and DI < 30 or LLk group.
The upper normal limits were 1.19 for TID and 1.23 for TID(ed) as established in 259 LLk patients. Both ratios increased with disease severity (P < .0001). Incidence of abnormal TID increased from 2% in normal patients to >36% in patients with severe CAD. Similarly, when DI was used to classify disease severity, the average ratios showed significant increasing trend with DI increase (P < .003); incidence of abnormal TID also increased with increasing DI. The incidence of abnormal TID in the group with high perfusion scores significantly increased compared to the group with low perfusion scores (stress total perfusion deficit, TPD < 3%) (P < .0001). The sensitivity for detecting severe CAD improved for TID when added to mild to moderate perfusion abnormality (3% ≤ TPD < 10%): 71% vs 64%, P < .05; and trended to improve for TID(ed)/TID(es): 69% vs 64%, P = .08, while the accuracy remained consistent if abnormal TID was considered as a marker in addition to stress TPD. Similar results were obtained when DI was used for the definition of severe CAD (sensitivity: 76% vs 66%, P < .05 when TID was combined with stress TPD).
TID ratios obtained from gated or ungated Mibi-Mibi MPS and are useful markers of severe CAD.
Journal of Nuclear Cardiology 03/2012; 19(3):465-73. · 2.67 Impact Factor
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ABSTRACT: Xanthine oxidase-derived superoxide production and oxidative stress contribute to the development of diabetic complications including diabetic cardiomyopathy. We hypothesized that xanthine oxidase-inhibitor allopurinol (ALP) may decrease hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis, and attenuate the development of left ventricle (LV) diastolic dysfunction in rats with streptozotocin (STZ)-induced diabetes.
Control Sprague Dawley (C) or streptozotocin-induced diabetic (D) rats were either untreated or treated with allopurinol (100 mg/kg/day) for 4 weeks starting at 1 week after streptozotocin injection. Free 15-F2t-isoprostane, a specific indicator of oxidative stress was measured by enzymatic immunoassay. The cardiomyocyte cross-sectional area was assessed by hematoxylin and eosin-stained paraffin-embedded sections of LVs. Myocardial collagens I and III were assessed by immunol histochemistry and Western blotting. Echocardiography was performed to characterize cardiac structure and function.
In diabetic rats, both plasma and cardiac tissue levels of free 15-F2t-isoprostane were increased (p < 0.05 vs. control), accompanied with significant increase (p < 0.05 vs. control) in cross-section area and myocardial collagen deposition of LV cardiomyocyte. Echocardiography in diabetic rats showed that LV weight/body weight ratio was significantly higher than in control rats, whereas the levels of LV end-diastolic volume and stroke volume were decreased (all p < 0.05 diabetic vs. control). All these changes were either attenuated or prevented by allopurinol. In addition, LV ejection fraction in diabetic rats treated with allopurinol was higher than that in untreated diabetic rats (p < 0.05).
Allopurinol can attenuate hyperglycemia-induced oxidative stress, ameliorate cardiomyocyte hypertrophy and fibrosis and subsequently prevent left ventricular dysfunction in early diabetes.
Diabetes/Metabolism Research and Reviews 03/2012; 28(5):409-17. · 3.37 Impact Factor
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ABSTRACT: Little is known about the prevalence and cardiovascular risk factors for prehypertension and hypertension in the She ethnic minority population of Fujian province in China.
Between April 2009 and September 2009, 5,523 participants of She nationality aged between 20 and 80 years participated in this survey and 5,357 were eventually enrolled in analyses. The survey was carried out to assess blood pressure and cardiovascular risk factors. The prevalence of prehypertension and hypertension was 35.87 and 38.42%, respectively, in all participants. Only 26.63% of the subjects with hypertension were aware of their diagnosis. Multivariate logistic regression showed that age, gender, overweight/obesity, dyslipidemia and alcohol use were risk factors for prehypertension, and age, overweight/obesity, dyslipidemia, alcohol use, family history of hypertension and hyperuricemia were risk factors for hypertension. The clustering of 2 and ≥ 3 risk factors was in higher proportion for subjects with hypertension and prehypertension when compared with those with prehypertension and normotension, respectively. After adjusting for other confounding factors, multivariable logistic regression showed that the greater the number of clustering cardiovascular risk factors, the greater the odds ratios for prehypertension and hypertension are.
Hypertension and prehypertension were common in the She population of Fujian province. Cardiovascular risk factors cluster during prehypertension and awareness of hypertension was minimal. Early lifestyle modifications could be advocated to prevent the transition from prehypertension to hypertension and cardiovascular disease.
Kidney and Blood Pressure Research 03/2012; 35(5):305-13. · 1.46 Impact Factor
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Min Ling,
Yuan Li, Yuan Xu,
Ying Pang,
Lu Shen,
Rongrong Jiang,
Yue Zhao,
Xiaojun Yang,
Jianping Zhang,
Jianwei Zhou,
Xinru Wang,
Qizhan Liu
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ABSTRACT: After acute exposure of cells to arsenic, reactive oxygen species mediate changes in cell behavior, including activation of proliferative signaling. For chronic exposure to arsenic, however, the function of reactive oxygen species in cell transformation remains poorly understood. Although microRNA-21 (miR-21) has been implicated in various aspects of carcinogenesis, its functions and molecular mechanisms in carcinogen-induced tumorigenesis are unclear. The purpose of this study was to determine if miR-21 is involved in arsenite-induced malignant transformation and to characterize the associated signaling pathways. During arsenite-induced transformation of human embryo lung fibroblast (HELF) cells, miR-21 was upregulated, and the extracellular signal-regulated kinase (ERK)/nuclear factor-κB (NF-κB) signal pathway was activated. Moreover, superoxide radical dismutase (a scavenger of superoxide) and catalase (a scavenger of hydroperoxides) blocked the arsenite-induced effects in HELF cells and mouse embryonic fibroblasts. Blockage of ERK by the inhibitor U0126 or inhibition of NF-κB p65 by siRNA or Bay 11-7082 prevented the increases in miR-21 and the decreases in Spry1, Pten, and Pdcd4, the target proteins of miR-21, induced by arsenite. As determined by a ChIP-qPCR assay, NF-κB p65 regulated miR-21 expression by binding directly to the promoter of miR-21. Further, anti-miR-21 downregulated miR-21 expression and prevented the arsenite-induced activation of ERK via the increase in Spry1, indicating that miR-21 has a feedback effect in regulating ERK activation. Overexpression of miR-21 with an miR-21 mimic and feedback activation of ERK and NF-κB via the decrease in Spry1 promoted the malignancy of HELF cells exposed to arsenite, but knockdown of miR-21 with anti-miR-21 and feedback blockage of ERK and NF-κB activation through an increase in Spry1 decreased anchorage-independent growth of arsenite-transformed cells. Thus, the transformation of HELF cells induced by chronic exposure to arsenite is mediated by increased miR-21 expression, which, in turn, is mediated by reactive oxygen species activation of the ERK/NF-κB pathway.
Free radical biology & medicine 02/2012; 52(9):1508-18. · 5.42 Impact Factor
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ABSTRACT: A radical solution: A Bu(4) NI/tert-butyl hydroperoxide (TBHP) catalyzed synthesis of amides through a cross-coupling reaction between acyl and aminyl radicals is described. This method involves the combination of aldehyde CH bond functionalization and decarbonylation of N,N-disubstituted formamides. The cross-coupling is metal-free, has a wide substrate scope, operational simplicity, and gives high yields on scale-up.
Angewandte Chemie International Edition 02/2012; 51(13):3231-5. · 13.45 Impact Factor
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Yuan Li,
Yue Zhao,
Rongrong Jiang, Yuan Xu,
Min Ling,
Ying Pang,
Lu Shen,
Yun Zhou,
Jianping Zhang,
Jianwei Zhou,
Xinru Wang,
Qizhan Liu
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ABSTRACT: When cells encounter genotoxic stress, sensors for DNA lesions stabilize and activate p53; the signals involved, however, are largely unclear. Inorganic arsenite is a ubiquitous environmental contaminant associated with an increased risk of lung and skin damage and cancer. Although DNA double-strand breaks and apoptosis may relate to arsenite-induced damage and carcinogenesis, the mechanism of action remains obscure. Here, we find that, in human embryo lung fibroblast (HELF) cells, arsenite induces the activation of dependent protein kinase catalytic subunit (DNA-PKcs), which then phosphorylates and activates c-Jun N-terminal kinases 2 (JNK2), but not JNK1. As a positive regulator of p53, JNK2 binds to p53 and prevents p53 from murine double minute 2 (mdm2)-mediated, ubiquitin-proteasome-dependent degradation. Knockdown of DNA-PKcs/JNK2 signal pathway or p53 reduces apoptosis but elevates the DNA damage induced by a high level of arsenite. These results suggest that DNA-PKcs-mediated stabilization of p53 by JNK2 is involved in arsenite-induced DNA damage and apoptosis.
Toxicology Letters 02/2012; 210(3):302-10. · 3.23 Impact Factor
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ABSTRACT: Tools for automated quantification of myocardial perfusion are available to nuclear cardiology practitioners and researchers. These methods have demonstrated superior reproducibility with comparable diagnostic and prognostic performance, when compared with segmental visual scoring by expert observers. A particularly useful application of the quantitative analysis can be in the detection of subtle changes or in precise determination of ischemia. Some challenges remain in the routine application of perfusion quantification. Multiple quantitative parameters may need to be reconciled by the expert reader for the final diagnosis. Computer analysis may be sensitive to imaging artifacts, resulting in false positive scans. Perfusion quantification may require site specific normal limits and some degree of manual interaction. New software improvements have been proposed to address some of these challenges.
Journal of Nuclear Cardiology 02/2012; 19(2):338-46. · 2.67 Impact Factor
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Yinghua Lin, Yuan Xu,
Gang Chen,
Xiaolan Lai,
Baoying Huang,
Zichun Chen,
Longteng Yao,
Shaoheng Zhu,
Jin Yao,
Junping Wen,
Huibin Huang,
Caijing Lin
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ABSTRACT: According to recent reports, the development of type 2 diabetes in China has soared at an alarming rate. However, most of the investigations were based on Han people, who account for the majority of people in China. Little is known about the prevalence of diabetes its chronic complications in the She people, who have their own traditional lifestyle and hereditable background, different from other Asian population. The present study investigated the prevalence of type 2 diabetes and associated risk factors in the adult population of She nationals.
A total of 5,385 participants entered into the analysis eventually, including 2,308 men and 3,077 women. An oral glucose tolerance test was performed in subjects without diagnosed diabetes. Liver function, cardiovascular risk (brachial-ankle pulse wave velocity, estimated glomerular filtration rate, and abnormal Minnesota codes findings), uric acid, and neuropathy were tested to assess the profiles of associated risks.
In general, the self-reported diabetes rate was 9.5%. After age and sex standardization, the prevalence of diabetes was 6.1% (6.7% for men and 5.7% for women) in She Chinese people. In logistic regression models, age, family history of diabetes, alcohol use, total cholesterol, and triglycerides were all significantly associated with the risk of diabetes in this cross-sectional study (all P<0.05). In all, 47.4% had cardiovascular risks, 19.4% had liver dysfunction, and 6.2% had hyperuricemia. For women, compared with the first quartile, log-transformed homeostasis model assessment for insulin resistance of the fourth quartile was significantly higher (P<0.05), and log-transformed homeostasis model assessment for β cells was also higher in the second, third, and fourth quartiles (all P<0.05). The prevalences of polyneuropathy in impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG/IGT, and diabetes mellitus (DM) were 16.1%, 13.1%, 18.6%, and 28.4% separately, which was higher than that in normal glucose tolerance. The prevalences of polyneuropathy in IFG/IGT and DM were higher than that in IGT.
The present study revealed that a total of 6.1% She people suffered from type 2 diabetes, which was lower than the average level of China, but the standardized prevalence of prediabetes was higher, 20.6%. Early peripheral neuropathy screening should be performed in the prediabetes population. The Toronto Clinical Neuropathy Scoring System is convenient to assess diabetic polyneuropathy in clinical practice and should be tested regularly for people in prediabetes. Liver dysfunction, headache, and insomnia, appearing before type 2 diabetes, should be assessed regularly to avoid deterioration.
Diabetes Technology & Therapeutics 02/2012; 14(5):430-9. · 1.93 Impact Factor
