Increased perioperative b-type natriuretic peptide associates with heart failure hospitalization or heart failure death after coronary artery bypass graft surgery.

BACKGROUND: Heart failure (HF) is a leading cause of hospitalization and mortality. Plasma B-type natriuretic peptide (BNP) is an established diagnostic and prognostic ambulatory HF biomarker. We hypothesized that increased perioperative BNP independently associates with HF hospitalization or HF death up to 5 yr after coronary artery bypass graft surgery. METHODS: The authors conducted a two-institution, prospective, observational study of 1,025 subjects (mean age = 64 ± 10 yr SD) undergoing isolated primary coronary artery bypass graft surgery with cardiopulmonary bypass. Plasma BNP was measured preoperatively and on postoperative days 1-5. The study outcome was hospitalization or death from HF, with HF events confirmed by reviewing hospital and death records. Cox proportional hazards analyses were performed with multivariable adjustments for clinical risk factors. Preoperative and peak postoperative BNP were added to the multivariable clinical model in order to assess additional predictive benefit. RESULTS: One hundred five subjects experienced an HF event (median time to first event = 1.1 yr). Median follow-up for subjects who did not have an HF event = 4.2 yr. When individually added to the multivariable clinical model, higher preoperative and peak postoperative BNP concentrations each, independently associated with the HF outcome (log10 preoperative BNP hazard ratio = 1.93; 95% CI, 1.30-2.88; P = 0.001; log10 peak postoperative BNP hazard ratio = 3.38; 95% CI, 1.45-7.65; P = 0.003). CONCLUSIONS: Increased perioperative BNP concentrations independently associate with HF hospitalization or HF death during the 5 yr after primary coronary artery bypass graft surgery. Clinical trials may be warranted to assess whether medical management focused on reducing preoperative and longitudinal postoperative BNP concentrations associates with decreased HF after coronary artery bypass graft surgery.

Inferring genetic causal effects on survival data with associated endo-phenotypes.

Age-at-onset phenotypes are important traits in genetic association analyses. Often, intermediate phenotypes that are related to the age-at-onset phenotype are also associated with the marker loci that are associated with the age-at-onset phenotype. In order to understand the genetic etiology of the observed associations, statistical methodology is needed to distinguish between a direct genetic effect on the age-at-onset phenotype and an indirect effect induced by the genetic association with the endo-phenotype that is correlated with the age-at-onset phenotype. In this communication, we introduce a new statistical approach to detect causal genetic effects on survival data in the presence of genetic associations with secondary phenotypes that might influence survival as well and thereby induce seemingly causal relationships. Derived using causal inference methodology, the proposed method is based on standard statistical methodology and can be implemented straight-forwardly, using standard software. Using simulation studies, the theoretical properties of the approach are verified and the power is assessed under realistic scenarios. The practical relevance of the approach is illustrated by an application to survival after cardiac surgery, where genetic components of myocardial infarctions are determined to not influence post-surgery hospital duration except through the MI-pathway.

Polymorphism in the protease-activated receptor-4 gene region associates with platelet activation and perioperative myocardial injury.

Protease-activated receptors (PAR)-1 and -4 are the principal receptors for thrombin-mediated platelet activation. Functional genetic variation has been described in the human PAR1 gene, but not in the PAR4 gene (F2RL3). We sought to identify variants in and around F2RL3 and to determine their association with perioperative myocardial injury (PMI) after coronary artery bypass graft surgery. We further explored possible mechanisms for F2RL3 single nucleotide polymorphism (SNP) associations with PMI including altered receptor expression and platelet activation. Twenty-three SNPs in the F2RL3 gene region were genotyped in two phases in 934 Caucasian subjects. Platelets from 43 subjects (23 major allele, 20 risk allele) homozygous for rs773857 (SNP with the strongest association with PMI) underwent flow cytometry to assess PAR4 receptor number and response to activation by a specific PAR4 activating peptide (AYPGKF) measured by von Willebrand factor (vWf) binding and P-selectin release and PAC-1 binding. We identified a novel association of SNP rs773857 with PMI (OR = 2.4, P = 0.004). rs773857 risk allele homozygotes have significantly increased platelet counts and platelets showed a significant increase in P-selectin release after activation (P = 0.004). We conclude that rs773857 risk allele homozygotes are associated with risk for increased platelet count and hyperactivity.

Does rotational thromboelastometry (ROTEM) improve prediction of bleeding after cardiac surgery?

BACKGROUND: Coagulopathy and massive bleeding are severe complications of cardiac surgery, particularly in procedures requiring prolonged cardiopulmonary bypass (CPB). There is huge variability in transfusion practices across hospitals and providers in cross-sectional studies. This variability may indicate unguided decision-making, perhaps attributable to lack of reliable, predictive laboratory testing of coagulopathy to guide transfusion practice. Rotational thromboelastometry (ROTEM) measures multiple coagulation parameters and may provide value from its ease of use, rapid results, and measurement of several steps in the coagulation pathway. Yet, the predictive value and utility of ROTEM remains unclear. In this study, we investigated ROTEM's predictive value for chest tube drainage after cardiac surgery. METHODS: Three hundred twenty-one patients undergoing cardiac surgery involving CPB were enrolled. Patient data were obtained from medical records, including chest tube output (CTO) from post-CPB through the first 8 postoperative hours. Perioperative and postoperative blood samples were collected for ROTEM analysis. Three measures of CTO were used as the primary end points for assessing coagulopathy: (i) continuous CTO; (ii) CTO dichotomized at 600 mL (75th percentile); and (iii) CTO dichotomized at 910 mL (90th percentile). Clinical and hematological variables, excluding ROTEM data, that were significantly correlated (P < 0.05) with continuous CTO were included in a stepwise regression model (model 1). An additional model that contained ROTEM variables in addition to the variables from model 1 was created (model 2). Significance in subsequent analyses was declared at P < 0.0167 to account for the 3 CTO end points. Net reclassification index was used to assess overall value of ROTEM data. RESULTS: For continuous CTO, ROTEM variables improved the model's predictive ability (P < 0.0001). For CTO dichotomized at 600 mL (75th percentile), ROTEM did not improve the area under the receiver operating characteristic curve (AUC) (P = 0.03). Similarly, for CTO dichotomized at 910 mL (90th percentile), ROTEM did not improve the AUC (P = 0.23). Net reclassification index similarly indicated that ROTEM results did not improve overall classification of patients (P = 0.12 for CTO ≥600 mL; P = 0.08 for CTO ≥910 mL). CONCLUSIONS: These results suggest that ROTEM data do not substantially improve a model's ability to predict chest tube drainage, beyond frequently used clinical and laboratory parameters. Although several ROTEM parameters were individually associated with CTO, they did not significantly improve goodness of fit when added to statistical models comprising only clinical and routine laboratory parameters. ROTEM does not seem to improve prediction of chest tube drainage after cardiac surgery involving CPB, although its use in guiding transfusion during cardiac surgery remains to be determined.

Chromosome 9p21 variant predicts mortality after coronary artery bypass graft surgery.

BACKGROUND: Recent genome-wide association studies have identified several chromosome 9p21 single nucleotide polymorphisms associated with coronary artery disease and myocardial infarction in nonsurgical populations. We have recently demonstrated an independent association between these 9p21 variants and perioperative myocardial injury after isolated primary coronary artery bypass graft (CABG) surgery. This study investigated the association of a 9p21 variant with mortality in patients after CABG surgery and its prognostic value to improve the EuroSCORE. METHODS AND RESULTS: In a 2-center, prospective, observational study of 846 white primary CABG surgery patients, we genotyped rs10116277, the 9p21 variant with the strongest association to perioperative myocardial injury in our cohort. To estimate the utility of rs10116277 for predicting all-cause mortality within 5 years after surgery, a Cox proportional hazard model was constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) while adjusting for demographics and clinical covariates. The homozygote minor allele of rs10116277 was associated with significantly increased risk of all-cause mortality even after adjusting for other clinical predictors of mortality in a Cox proportional hazards model (HR, 1.7; 95% CI, 1.1-2.7; P=0.026). Addition of rs10116277 to the logistic EuroSCORE also significantly improved model prediction for mortality (HR, 1.82; 95% CI, 1.15-2.88; P=0.01). CONCLUSIONS: The 9p21 variant rs10116277 is independently associated with all-cause mortality after primary CABG surgery in whites and significantly improves the predictive value of the logistic EuroSCORE. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00281164.

Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women.

OBJECTIVES: Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2). METHODS: We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs). RESULTS: There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction > or =0.25). There was also no association with any of the haplotypes examined (p > or = 0.15) and no evidence of joint effects of variants in the 5 genes (p > or = 0.51). CONCLUSION: Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1, and HSD17B2 and risk for developing colorectal cancer.

Preoperative C-reactive protein predicts long-term mortality and hospital length of stay after primary, nonemergent coronary artery bypass grafting.

BACKGROUND: Preoperative C-reactive protein (CRP) levels more than 10 mg/l have been shown to be associated with increased morbidity and mortality after cardiac surgery. We examine the value of preoperative CRP levels less than 10 mg/l for predicting long-term, all-cause mortality and hospital length of stay in surgical patients undergoing primary, nonemergent coronary artery bypass graft-only surgery. METHODS: We examined the association between preoperative CRP levels stratified into four categories (< 1, 1-3, 3-10, and > 10 mg/l), and 7-yr all-cause mortality and hospital length of stay in 914 prospectively enrolled primary, nonemergent coronary artery bypass graft-only surgical patients using a proportional hazards regression model. RESULTS: Eighty-seven patients (9.5%) died during a mean follow-up period of 4.8 +/- 1.5 yr. After proportional hazards adjustment, the 3-10 and > 10 mg/l preoperative CRP groups were associated with long-term, all-cause mortality (hazards ratios [95% CI]: 2.50 [1.22-5.16], P = 0.01 and 2.66 [1.21-5.80], P = 0.02, respectively) and extended hospital length of stay (1.32 [1.07-1.63], P < 0.001 and 1.27 [1.02-1.62], P = 0.001, respectively). CONCLUSION: We demonstrate that preoperative CRP levels as low as 3 mg/l are associated with increased long-term mortality and extended hospital length of stay in relatively lower-acuity patients undergoing primary, nonemergent coronary artery bypass graft-only surgery. These important findings may allow for more objective risk stratification of patients who present for uncomplicated surgical coronary revascularization.

Comparison of the utility of preoperative versus postoperative B-type natriuretic peptide for predicting hospital length of stay and mortality after primary coronary artery bypass grafting.

BACKGROUND: Preoperative B-type natriuretic peptide (BNP) is known to predict adverse outcomes after cardiac surgery. The value of postoperative BNP for predicting adverse outcomes is less well delineated. The authors hypothesized that peak postoperative plasma BNP (measured postoperative days 1-5) predicts hospital length of stay (HLOS) and mortality in patients undergoing primary coronary artery bypass grafting, even after adjusting for preoperative BNP and perioperative clinical risk factors. METHODS: This study is a prospective longitudinal study of 1,183 patients undergoing primary coronary artery bypass grafting surgery. Mortality was defined as all-cause death within 5 yr after surgery. Cox proportional hazards analyses were conducted to separately evaluate the associations between peak postoperative BNP and HLOS and mortality. Multivariable adjustments were made for patient demographics, preoperative BNP concentration, and clinical risk factors. BNP measurements were log10 transformed before analysis. RESULTS: One hundred fifteen deaths (9.7%) occurred in the cohort (mean follow-up = 4.3 yr, range = 2.38-5.0 yr). After multivariable adjustment for preoperative BNP and clinical covariates, peak postoperative BNP predicted HLOS (hazard ratio [HR] = 1.28, 95% CI = 1.002-1.64, P = 0.049) but not mortality (HR = 1.62, CI = 0.71-3.68, P = 0.25), whereas preoperative BNP independently predicted HLOS (HR = 1.09, CI = 1.01-1.18, P = 0.03) and approached being an independent predictor of mortality (HR = 1.36, CI = 0.96-1.94, P = 0.08). When preoperative and peak postoperative BNP were separately adjusted for within the clinical multivariable models, each independently predicted HLOS (preoperative BNP HR = 1.13, CI = 1.05-1.21, P = 0.0007; peak postoperative BNP HR = 1.44, CI = 1.15-1.81, P = 0.001) and mortality (preoperative BNP HR = 1.50, CI = 1.09-2.07, P = 0.01; peak postoperative BNP HR = 2.29, CI = 1.11-4.73, P = 0.02). CONCLUSIONS: Preoperative BNP may be better than peak postoperative BNP for predicting HLOS and longer term mortality after primary coronary artery bypass grafting surgery.

Heart-type fatty acid binding protein is an independent predictor of death and ventricular dysfunction after coronary artery bypass graft surgery.

BACKGROUND: Heart-type fatty acid binding protein (hFABP) functions as a myocardial fatty acid transporter and is released into the circulation early after myocardial injury. We hypothesized that hFABP is superior to conventional cardiac biomarkers for predicting early perioperative myocardial injury after coronary artery bypass graft (CABG) surgery. METHODS: A prospective cohort study of 1298 patients undergoing primary CABG with cardiopulmonary bypass (CPB) was performed at 2 institutions. Four plasma myocardial injury biomarkers (hFABP; cardiac troponin I [cTnI]; creatine kinase, MB [CK-MB] fraction; and myoglobin) were measured at 7 perioperative time points. The association among perioperative cardiac biomarkers and ventricular dysfunction, hospital length of stay (HLOS), and up to 5-year postoperative mortality (median 3.3 years) was assessed using Cox proportional hazard models. We defined in-hospital ventricular dysfunction as a new requirement for 2 or more inotropes, or new placement of an intraaortic balloon pump, or ventricular assist device either during the intraoperative period after the patient separated from CPB or postoperatively in the intensive care unit. RESULTS: The positive and negative predictive values of mortality for hFABP are 13% (95% confidence interval [CI], 9%-19%) and 95% (95% CI, 94%-96%), respectively, which is higher than for cTnI and CK-MB. After adjusting for clinical predictors, both postoperative day (POD) 1 and peak hFABP levels were independent predictors of ventricular dysfunction (P < 0.0001), HLOS (P < 0.05), and 5-year mortality (P < 0.0001) after CABG surgery. Furthermore, POD1 and peak hFABP levels were significantly superior to other evaluated biomarkers for predicting mortality. In a repeated-measures analysis, hFABP outperformed all other models of fit for HLOS. Patients with POD2 hFABP levels higher than post-CPB hFABP levels had an increased mortality compared with those patients whose POD2 hFABP levels decreased from their post-CPB level (hazard ratio, 10.9; 95% CI, 5.0-23.7; P = 7.2 × 10(-10)). Mortality in the 120 patients (10%) with a later hFABP peak was 18.3%, compared with 4.7% in those who did not peak later. Alternatively, for cTnI or CK-MB, no difference in mortality was detected. CONCLUSION: Compared with traditional markers of myocardial injury after CABG surgery, hFABP peaks earlier and is a superior independent predictor of postoperative mortality and ventricular dysfunction.

Plasma neutrophil gelatinase-associated lipocalin and acute postoperative kidney injury in adult cardiac surgical patients.

BACKGROUND: Acute kidney injury (AKI) after coronary artery bypass graft (CABG) surgery is associated with increased postoperative morbidity and mortality. We hypothesized that increased plasma neutrophil gelatinase-associated lipocalin (NGAL) measured immediately after separating from cardiopulmonary bypass (CPB) would predict AKI after CABG surgery. METHODS: In a retrospective observational study, we examined the value of plasma NGAL measured after CPB for predicting the risk of developing AKI (defined as a > or = 50% increase in serum creatinine from preoperative levels) in 879 patients after CABG surgery using multivariable logistic regression. Area under the curve of receiver operating characteristic curves was analyzed to assess sensitivities, specificities, and cutoff points for postoperative plasma NGAL levels to predict AKI. RESULTS: Seventy-five patients (8.6%) developed postoperative AKI. Plasma NGAL levels measured after CPB were higher in patients who subsequently developed AKI than in those who did not (AKI: 268.8 ng/mL [207.5-459.5 ng/mL], median [interquartile range], vs no AKI: 238.4 ng/mL [172.0-319.1 ng/mL]; P < 0.001) and remained higher through postoperative day 4. An optimal serum plasma NGAL cutoff of 353.5 ng/mL at the post-CPB time point had a sensitivity of 38.7%, specificity of 81.5%, and a positive predictive value of 16.3% for predicting AKI. In our multivariate regression model, post-CPB plasma NGAL levels >353.5 ng/mL were independently associated with postoperative AKI (odds ratio, 2.3; 95% confidence interval, 1.5-6.5; P = 0.002). CONCLUSION: An early increase of post-CPB plasma NGAL is associated with AKI in adult patients undergoing CABG surgery, although the sensitivity is low. Therefore, assessing early plasma NGAL alone has limited utility for predicting AKI in this patient population.

Postoperative activity, but not preoperative activity, of antithrombin is associated with major adverse cardiac events after coronary artery bypass graft surgery.

BACKGROUND: Low levels of antithrombin (AT) have been independently associated with prolonged intensive care unit stay and an increased incidence of neurologic and thromboembolic events after cardiac surgery. We hypothesized that perioperative AT activity is independently associated with postoperative major adverse cardiac events (MACEs) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: We prospectively studied 1403 patients undergoing primary CABG surgery with cardiopulmonary bypass (CPB) (http://clinicaltrials.gov/show/NCT00281164). The primary clinical end point was occurrence of MACE, defined as a composite outcome of any one or more of the following: postoperative death, reoperation for coronary graft occlusion, myocardial infarction, stroke, pulmonary embolism, or cardiac arrest until first hospital discharge. Plasma AT activity was measured before surgery, after post-CPB protamine, and on postoperative days (PODs) 1-5. Multivariate logistic regression modeling was performed to estimate the independent effect of perioperative AT activity upon MACE. RESULTS: MACE occurred in 146 patients (10.4%), consisting of postoperative mortality (n = 12), myocardial infarction (n = 108), stroke (n = 17), pulmonary embolism (n = 8), cardiac arrest (n = 16), or a subsequent postoperative or catheter-based treatment for graft occlusion (n = 6). AT activity at baseline did not differ between patients with (0.91 ± 0.13 IU/mL; n = 146) and without (0.92 ± 0.13 IU/mL; n = 1257) (P = 0.18) MACE. AT activity in both groups was markedly reduced immediately after CPB and recovered to baseline values over the ensuing 5 PODs. Postoperative AT activity was significantly lower in patients with MACE than those without MACE. After adjustment for clinical predictors of MACE, AT activity on PODs 2 and 3 was associated with MACE. CONCLUSIONS: Preoperative AT activity is not associated with MACE after CABG surgery. MACE is independently associated with postoperative AT activity but only at time points occurring predominantly after the MACE.

Troponin is superior to electrocardiogram and creatinine kinase MB for predicting clinically significant myocardial injury after coronary artery bypass grafting.

AIMS: Cardiac biomarkers are routinely elevated after uncomplicated cardiac surgery to levels considered diagnostic of myocardial infarction in ambulatory populations. We investigated the diagnostic power of electrocardiogram (ECG) and cardiac biomarker criteria to predict clinically relevant myocardial injury using benchmarks of mortality and increased hospital length of stay (HLOS) in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS AND RESULTS: Perioperative ECGs, creatinine kinase MB fraction, and cardiac troponin I (cTnI) were assessed in 545 primary CABG patients. None of the ECG criteria for myocardial injury predicted mortality or HLOS. However, post-operative day (POD) 1 cTnI levels independently predicted 5-year mortality (hazard ratio = 1.42; 95% CI 1.14-1.76 for each 10 microg/L increase; P = 0.009), while adjusting for baseline demographic characteristics and perioperative risk factors. Moreover, cTnI was the only biomarker that significantly improved the prediction of 5-year mortality estimated by the logistic Euroscore (P = 0.02). Furthermore, the predictive value of cTnI for 5-year mortality was replicated in a separately collected cohort of 1031 CABG patients using cardiac troponin T. CONCLUSION: Electrocardiogram diagnosis of post-operative myocardial injury after CABG does not independently predict an increased risk of 5-year mortality or HLOS. Conversely, cTnI is independently associated with an increased risk of mortality and prolonged HLOS.

Transcriptional profiling reveals developmental relationship and distinct biological functions of CD16+ and CD16- monocyte subsets.

BACKGROUND: Human peripheral blood monocytes (Mo) consist of subsets distinguished by expression of CD16 (FCgammaRIII) and chemokine receptors. Classical CD16- Mo express CCR2 and migrate in response to CCL2, while a minor CD16+ Mo subset expresses CD16 and CX3CR1 and migrates into tissues expressing CX3CL1. CD16+ Mo produce pro-inflammatory cytokines and are expanded in certain inflammatory conditions including sepsis and HIV infection. RESULTS: To gain insight into the developmental relationship and functions of CD16+ and CD16- Mo, we examined transcriptional profiles of these Mo subsets in peripheral blood from healthy individuals. Of 16,328 expressed genes, 2,759 genes were differentially expressed and 228 and 250 were >2-fold upregulated and downregulated, respectively, in CD16+ compared to CD16- Mo. CD16+ Mo were distinguished by upregulation of transcripts for dendritic cell (DC) (SIGLEC10, CD43, RARA) and macrophage (MPhi) (CSF1R/CD115, MafB, CD97, C3aR) markers together with transcripts relevant for DC-T cell interaction (CXCL16, ICAM-2, LFA-1), cell activation (LTB, TNFRSF8, LST1, IFITM1-3, HMOX1, SOD-1, WARS, MGLL), and negative regulation of the cell cycle (CDKN1C, MTSS1), whereas CD16- Mo were distinguished by upregulation of transcripts for myeloid (CD14, MNDA, TREM1, CD1d, C1qR/CD93) and granulocyte markers (FPR1, GCSFR/CD114, S100A8-9/12). Differential expression of CSF1R, CSF3R, C1QR1, C3AR1, CD1d, CD43, CXCL16, and CX3CR1 was confirmed by flow cytometry. Furthermore, increased expression of RARA and KLF2 transcripts in CD16+ Mo coincided with absence of cell surface cutaneous lymphocyte associated antigen (CLA) expression, indicating potential imprinting for non-skin homing. CONCLUSION: These results suggest that CD16+ and CD16- Mo originate from a common myeloid precursor, with CD16+ Mo having a more MPhi - and DC-like transcription program suggesting a more advanced stage of differentiation. Distinct transcriptional programs, together with their recruitment into tissues via different mechanisms, also suggest that CD16+ and CD16- Mo give rise to functionally distinct DC and MPhi in vivo.

C-Reactive protein gene variants are associated with postoperative C-reactive protein levels after coronary artery bypass surgery.

BACKGROUND: Elevated baseline C-reactive protein (CRP) levels are associated with increased risk for developing cardiovascular disease. Several CRP gene variants have been associated with altered baseline CRP levels in ambulatory populations. However, the influence of CRP gene variants on CRP levels during inflammatory states, such as surgery, is largely unexplored. We describe the association between candidate CRP gene variants and postoperative plasma CRP levels in patients undergoing primary, elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). METHODS: Using a multicenter candidate gene association study design, we examined the association between seventeen candidate CRP single nucleotide polymorphisms (SNPs) and inferred haplotypes, and altered postoperative CRP levels in 604 patients undergoing CABG surgery with CPB. Perioperative CRP levels were measured immediately prior to surgery, post-CPB and on postoperative days (POD) 1-4. RESULTS: CRP levels were significantly elevated at all postoperative time points when compared with preoperative levels (P < 0.0001). After adjusting for clinical covariates, the minor allele of the synonymous coding SNP, rs1800947 was associated with lower peak postoperative CRP levels (P = 2.4 x 10(-4)) and lower CRP levels across all postoperative time points (P = 4.8 x 10(-5)). rs1800947 remained highly significant after Bonferroni adjustment for multiple comparisons. CONCLUSION: We identified a CRP gene SNP associated with lower postoperative CRP levels in patients undergoing CABG surgery with CPB. Further investigation is needed to clarify the significance of this association between CRP gene variants and the acute-phase rise in postoperative CRP levels with regard to the risk of adverse postoperative outcomes.

Natriuretic peptide system gene variants are associated with ventricular dysfunction after coronary artery bypass grafting.

BACKGROUND: Ventricular dysfunction (VnD) after primary coronary artery bypass grafting is associated with increased hospital stay and mortality. Natriuretic peptides have compensatory vasodilatory, natriuretic, and paracrine influences on myocardial failure and ischemia. The authors hypothesized that natriuretic peptide system gene variants independently predict risk of VnD after primary coronary artery bypass grafting. METHODS: A total of 1,164 patients undergoing primary coronary artery bypass grafting with cardiopulmonary bypass at two institutions were prospectively enrolled. After prospectively defined exclusions, 697 patients of European descent (76 with VnD) were analyzed. VnD was defined as need for at least 2 new inotropes and/or new mechanical ventricular support after coronary artery bypass grafting. A total of 139 haplotype-tagging single nucleotide polymorphisms (SNPs) within 7 genes (NPPA, NPPB, NPPC, NPR1, NPR2, NPR3, CORIN) were genotyped. SNPs univariately associated with VnD were entered into logistic regression models adjusting for clinical covariates predictive of VnD. To control for multiple comparisons, permutation analyses were conducted for all SNP associations. RESULTS: After adjusting for clinical covariates and multiple comparisons within each gene, seven NPPA/NPPB SNPs (rs632793, rs6668352, rs549596, rs198388, rs198389, rs6676300, rs1009592) were associated with decreased risk of postoperative VnD (additive model; odds ratios 0.44-0.55; P = 0.010- 0.036) and four NPR3 SNPs (rs700923, rs16890196, rs765199, rs700926) were associated with increased risk of postoperative VnD (recessive model; odds ratios 3.89-4.28; P = 0.007-0.034). CONCLUSIONS: Genetic variation within the NPPA/NPPB and NPR3 genes is associated with risk of VnD after primary coronary artery bypass grafting. Knowledge of such genotypic predictors may result in better understanding of the molecular mechanisms underlying postoperative VnD.

Filtration of nano-particles by a gas-solid fluidized bed.

The filtration of 80 nm SiO2 and Al(2)O(3) particles in a gas stream using fluidized beds was studied. Silica sand and activated carbon (A.C.) were adopted as bed materials to filtrate 80 nm SiO2 and Al(2)O(3) particles. The collected particles were elutriated from the fluidized bed, so the filtration was a dynamic process and the variations of the removal efficiency with time were studied. Experimental results showed that the filtrations of 80 nm SiO2 and Al(2)O(3) particles with a bed material of silica sand were not dynamic processes but the filtration by A.C. was. The removal efficiencies for SiO2 and Al(2)O(3) particles using silica sand as bed material were held steady and found to be equal, between 86 and 93%. A.C. is considered to be more efficient than silica sand because it has a high specific surface area. However, the experimental data yield conflicting results. The removal efficiency of Al(2)O(3) particles fell from 92% initially to 80% at the end of test-a little lower than that obtained by filtration using silica sand. A higher voidage of A.C. than silica sand weakens the removal of nanoparticles since the diffusion mechanism dominates. The removal efficiency of SiO2 by A.C. decayed from 83 to 40% with time passed. The huge differences between the filtration efficiency of SiO2 and that of Al(2)O(3) particles by A.C. was associated with the extensive segregation of SiO2 and A.C. particles, which caused more SiO2 particles to move to the top of the bed, where they were elutriated. The weak inter-particle force for SiO2 decreased the removal efficiency also.

Bayesian variable selection for gene expression modeling with regulatory motif binding sites in neuroinflammatory events.

Multiple transcription factors (TFs) coordinately control transcriptional regulation of genes in eukaryotes. Although numerous computational methods focus on the identification of individual TF-binding sites (TFBSs), very few consider the interdependence among these sites. In this article, we studied the relationship between TFBSs and microarray gene expression levels using both family-wise and memberspecific motifs, under various combination of regression models with Bayesian variable selection, as well as motif scoring and sharing conditions, in order to account for the coordination complexity of transcription regulation. We proposed a three-step approach to model the relationship. In the first step, we preprocessed microarray data and used p-values and expression ratios to preselect upregulated and downregulated genes. The second step aimed to identify and score individual TFBSs within DNA sequence of each gene. A method based on the degree of similarity and the number of TFBSs was employed to calculate the score of each TFBS in each gene sequence. In the last step, linear regression and probit regression were used to build a predictive model of gene expression outcomes using these TFBSs as predictors. Given a certain number of predictors to be used, a full search of all possible predictor sets is usually combinatorially prohibitive. Therefore, this article considered the Bayesian variable selection for prediction using either of the regression models. The Bayesian variable selection has been applied in the context of gene selection, missing value estimation, and regulatory motif identification. In our modeling, the regressor was approximated as a linear combination of the TFBSs and a Gibbs sampler was employed to find the strongest TFBSs. We applied these regression models with the Bayesian variable selection on spinal cord injury gene expression data set. These TFs demonstrated intricate regulatory roles either as a family or as individual members in neuroinflammatory events. Our analysis can be applied to create plausible hypotheses for combinatorial regulation by TFBSs and avoiding false-positive candidates in the modeling process at the same time. Such a systematic approach provides the possibility to dissect transcription regulation, from a more comprehensive perspective, through which phenotypical events at cellular and tissue levels are moved forward by molecular events at gene transcription and translation levels.

Mutual information-based feature selection in studying perturbation of dendritic structure caused by TSC2 inactivation.

In this study, the effect of protein Tuberous sclerosis 2 (TSC2) on the dendritic spine density and length was demonstrated by using TSC2-RNAinactivation. In addition, the role of rapamycin, an antagonist of the molecular target of rapamycin, in the morphological changes of spine caused by TSC2 silencing was investigated. The features were extracted from highresolution three-dimensional image stacks collected by two-photon laser scanning microscopy of green fluorescing pyramidal cells expressing TSC2-RNA interference (RNAi), or TSC2-RNAi and rapamycin treatment in rat hippocampal slice cultures. We proposed to apply the lognormal distribution method for feature extraction. The extracted features of three cases under investigation, namely, (1) green-fluorescent protein GFP vs TSC2-RNAi, (2) GFP vs TSC2-RNAi and rapamycin, and (3) TSC2-RNAi vs TSC2-RNAi and rapamycin, were analyzed by mutual information-based feature selection and evaluated by three classifiers, K-nearest neighbor, Perceptron, and two-layer neural networks. The results showed that both the spine density and length have significant morphological changes after TSC2-RNAi treatment. However, rapamycin treatment could reverse the effect of TSC2-RNAi on spine length but not on spine density. These results are consistent with the results reported in the scientific literature. Finally, we explored the application of pattern recognition method in a small sample with richer feature properties, namely bootstrap mutual information estimation and a mutual information- based feature selection method.

Thermal treatment of the fly ash from municipal solid waste incinerator with rotary kiln.

Reuse of the fly ash from the municipal solid waste incinerator (MSWI) is a policy of Taiwan EPA. However, the fly ash is often classified as a hazardous waste and cannot be reused directly because the concentrations of heavy metals exceed the TCLP regulations. The main objective of this study is to investigate the continuous sintering behavior of fly ash with a rotary kiln and seek a solution to reduce the concentrations of heavy metal to an acceptable value. The partitions of the heavy metals in the process are also considered. The results of TCLP showed that among the metals of Cr, Cd, Cu and Pb, only the concentrations of Pb in raw fly ash exceeded the regulation. At sintering temperatures of 700, 800 and 900 degrees C, the concentration of Pb decreased in sintering products, however, the concentration of Pb still exceeded the limitation at 700 and 800 degrees C. Additionally, the water-washing was used to pre-treat the fly ash before sintering process. The washing treatment effectively reduced the leaching concentrations of Pb to agree the regulations. Therefore, water-washing followed by a sintering treatment is an available process for detoxifying the fly ash of MSWI.

Linkage and association analyses of microsatellites and single-nucleotide polymorphisms in nuclear families.

Several simulation studies have suggested that a high-density single-nucleotide polymorphisms (SNPs) marker set may be as useful as a traditional microsatellites (MS) marker set in performing whole-genome linkage analysis. However, very few studies have directly tested the SNPs-based genome-wide scan. In the present study, we compared the linkage results from the SNPs-based scan with a map density of 3-cM spacing with those from the MS scan using a 10-cM marker set among 300 nuclear families each from the Aipotu (AI), Danacaa (DA), and Karangar (KA) populations from the simulated Genetic Analysis Workshop 14 Problem 2 data. We found that information contents obtained from the SNPs scan were somewhat lower than those from the MS scan. However, the linkage results obtained from the two scans showed a high degree of similarity. Both scans identified a similar number of chromosomal regions attaining nominal significance (p < 0.05). Specifically, both scans detected confirmed evidence for linkage (NPL >or= 4.07, p = 2 x 10(-5)) to chromosome 1 in the AI families, chromosomes 1 and 3 in the DA families, and chromosomes 3, 5, and 9 in the KA families. An additional confirmed linkage to chromosome 5 in the AI families was detected only by the MS scan. We also observed slightly wider 1-LOD intervals for more of the SNP peaks than for the MS peaks, which is likely due to lower information contents for the SNPs. Subsequent fine-mapping association analysis further identified 2 to 3 markers significantly associated with disease status in each population; B03T3056, B03T3058, and B05T4139 in the AI population, B03T3056 and B03T3058 in the KA population, and B03T3056, B03T3057, and B03T3058 in the DA population. Among the four markers, three were chosen based on results obtained from the two scans, but one was solely from the SNP scan. In summary, our finding suggests that the SNP-based genome scan has the potential to be as powerful as the traditional MS-based scan and offers good identification of peak location for further fine-mapped association analysis.