Christine De Staercke

Association between Depression and Inflammation - Differences by Race and Sex: The META-Health Study

Objective: To test whether the association between depression and inflammation differs by race and sex. Depressive symptoms have been associated with higher levels of C-reactive protein (CRP). However, few studies have examined this association in samples including a significant number of African Americans, or examined whether the association differs by race and sex. Methods: Depressive symptoms and CRP were assessed in 512 African American and white participants, age 30 to 65 years, as part of the community-based Morehouse and Emory Team up to Eliminate Health Disparities (META-Health) Study. Depression was determined by responses to the Beck Depression Inventory II (BDI-II). Multivariable linear regression models were used to adjust for demographic and metabolic risk factors. Results: African American men had higher total BDI-II scores than white men (p =.03), whereas there was no difference in women. There was a significant race-sex-depression interaction in predicting CRP levels (p =.02). White women with mild to severe depressive symptoms had higher levels of CRP compared with those with minimal to no depressive symptoms (p <.05). There were no differences in levels of CRP by severity of depressive symptoms in white men or African Americans of either sex. Higher BDI-II scores were related to higher CRP levels in white women after adjusting for age and level of education (&bgr; = 0.227, p =.006). However, the association was eliminated after further adjustment for metabolic risk factors (&bgr; = 0.077, p =.35). Conclusions: Although depressive symptoms are associated with inflammation, the association varies by race and sex.CVD = cardiovascular disease; BDI-II = Beck Depression Inventory II; CRP = C-reactive protein; BMI = body mass index; HDL-C = high-density lipoprotein cholesterol

Evidence for the transmission of parvovirus B19 in patients with bleeding disorders treated with plasma‐derived factor concentrates in the era of nucleic acid test screening

BACKGROUND: Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu‐like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission.

Elevated C-reactive protein is associated with severe periodic leg movements of sleep in patients with restless legs syndrome.

BACKGROUNDnRestless legs syndrome (RLS) is a common sleep disorder in which urges to move the legs are felt during rest, are felt at night, and are improved by leg movement. RLS has been implicated in the development of cardiovascular disease. Periodic leg movements (PLMs) may be a mediator of this relationship. We evaluated systemic inflammation and PLMs in RLS patients to further assess cardiovascular risk.nnnMETHODSn137 RLS patients had PLM measurements taken while unmedicated for RLS. Banked plasma was assayed for high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha).nnnRESULTSnMean (SD) PLM index was 19.3 (22.0). PLMs were unrelated to TNF-a and IL-6, but were modestly correlated with logCRP (r(129)=0.19, p=0.03). Those patients with at least 45PLMs/h had an odds ratio of 3.56 (95% CI 1.26-10.03, p=0.02, df=1) for having elevated CRP compared to those with fewer than 45PLMs/h. After adjustment for age, race, gender, diabetes, hypertension, hyperlipidemia, inflammatory disorders, CRP-lowering medications, and body mass index, the OR for those with ≥ 45PLMs/h was 8.60 (95% CI 1.23 to 60.17, p=0.03, df=10).nnnCONCLUSIONSnPLMs are associated with increased inflammation, such that those RLS patients with at least 45PLMs/h had more than triple the odds of elevated CRP than those with fewer PLMs. Further investigation into PLMs and inflammation is warranted.

Effects of storage-aged red blood cell transfusions on endothelial function in hospitalized patients.

Clinical and animal studies indicate that transfusions of older stored red blood cells (RBCs) impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of nitric oxide (NO)‐mediated vasodilation after transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients.

25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients

BackgroundCirculating 25-hydroxyvitamin D [25(OH)D] concentration is inversely associated with peripheral arterial disease and hypertension. Vascular remodeling may play a role in this association, however, data relating vitamin D level to specific remodeling biomarkers among ESRD patients is sparse. We tested whether 25(OH)D concentration is associated with markers of vascular remodeling and inflammation in African American ESRD patients.MethodsWe conducted a cross-sectional study among ESRD patients receiving maintenance hemodialysis within Emory University-affiliated outpatient hemodialysis units. Demographic, clinical and dialysis treatment data were collected via direct patient interview and review of patients records at the time of enrollment, and each patient gave blood samples. Associations between 25(OH)D and biomarker concentrations were estimated in univariate analyses using Pearsons correlation coefficients and in multivariate analyses using linear regression models. 25(OH) D concentration was entered in multivariate linear regression models as a continuous variable and binary variable (<15 ng/ml and ≥15 ng/ml). Adjusted estimate concentrations of biomarkers were compared between 25(OH) D groups using analysis of variance (ANOVA). Finally, results were stratified by vascular access type.ResultsAmong 91 patients, mean (standard deviation) 25(OH)D concentration was 18.8 (9.6) ng/ml, and was low (<15 ng/ml) in 43% of patients. In univariate analyses, low 25(OH) D was associated with lower serum calcium, higher serum phosphorus, and higher LDL concentrations. 25(OH) D concentration was inversely correlated with MMP-9 concentration (r = -0.29, p = 0.004). In multivariate analyses, MMP-9 concentration remained negatively associated with 25(OH) D concentration (P = 0.03) and anti-inflammatory IL-10 concentration positively correlated with 25(OH) D concentration (P = 0.04).ConclusionsPlasma MMP-9 and circulating 25(OH) D concentrations are significantly and inversely associated among ESRD patients. This finding may suggest a potential mechanism by which low circulating 25(OH) D functions as a cardiovascular risk factor.

The relationship between FV Leiden and pulmonary embolism

Pulmonary embolism (PE) is one of the leading causes of in-patient hospital deaths. As a consequence, the identification of hemostatic variables that could identify those at risk would be important in reducing mortality. It has previously been thought that deep vein thrombosis and PE are a single disease entity and would, therefore, have the same risk factors. This view is changing, however, with the realization that the prevalence of FV Leiden, a recognized genetic risk factor for deep vein thrombosis, may be a milder genetic risk factor for PE. These observations suggest that PE is not only associated with a different set of risk factors, but may be reflective of a different clot structure.Pulmonary embolism (PE) is one of the leading causes of in-patient hospital deaths. As a consequence, the identification of hemostatic variables that could identify those at risk would be important in reducing mortality. It has previously been thought that deep vein thrombosis and PE are a single disease entity and would, therefore, have the same risk factors. This view is changing, however, with the realization that the prevalence of FV Leiden, a recognized genetic risk factor for deep vein thrombosis, may be a milder genetic risk factor for PE. These observations suggest that PE is not only associated with a different set of risk factors, but may be reflective of a different clot structure.

Bleeding events are associated with an increase in markers of inflammation in acute coronary syndromes: an ACUITY trial substudy

Bleeding events have been associated with adverse early and late outcomes in virtually all clinical settings. The mechanism behind this observation remains poorly understood. We sought to determine if the reason might be the provocation of an inflammatory response by bleeding events. In a formal substudy of the ACUITY trial, plasma samples of a range of biomarkers were collected at baseline, discharge, 30xa0days, and 1xa0year from 192 patients with acute coronary syndromes (ACS) and were analyzed in a central core laboratory. Temporal changes in biomarker levels were assessed in patients who experienced in-hospital hemorrhagic events, recurrent ischemic events, or neither. Sixteen patients were excluded from the study (7 with incomplete samples, 5 undergoing coronary artery bypass grafting (CABG) during index hospitalization; 1 had both bleeding and ischemic events). Median high sensitivity C-reactive protein (hs-CRP) levels (mg/l) increased significantly more from admission to discharge among the 9 patients who experienced an in-hospital major bleed compared to either the 9 patients who had a recurrent ischemic event (+6.0 vs. +0.70, Pxa0=xa00.04) or the 151 patients who had no event (+6.0 vs. +0.60, Pxa0=xa00.003). Compared to patients with no in-hospital events, median interleukin-6 (IL-6) levels (pg/ml) increased from admission to hospital discharge non-significantly in those with a bleeding event (+0.92 vs. +2.46, Pxa0=xa00.55) and in those who experienced an in-hospital recurrent ischemic event (+0.92 vs. +3.60, Pxa0=xa00.09). These data suggest that major bleeding is associated with development of a pro-inflammatory state. If confirmed, this mechanism may in part explain the poor prognosis of patients experiencing an acute hemorrhagic event.

Mutations in the S4–H2 loop of eIF4E which increase the affinity for m7GTP

Eukaryotic initiation factor 4E (eIF4E) binds the 5′‐cap of eukaryotic mRNAs and overexpression of eIF4E in epithelial cell cancers correlates with the metastases/tissue invasion phenotype. Photolabeling of eIF4E with [γ‐32P]8‐azidoguanosine 5′‐triphosphate (8‐N3GTP) demonstrated cross‐linking at Lys‐119 in the S4–H2 loop which is distant from the m7GTP binding site [Marcotrigiano et al. (1997) Cell 89, 951–961; Friedland et al. (1997) Protein Sci. 6, 125–131]. Modeling studies indicate that 8‐N3GTP cross‐linked with Lys‐119 because it binds a site that is occupied by the second nucleotide of a bound mRNA. Mutagenesis of the S4–H2 loop produced proteins with a 5–10‐fold higher affinity for m7GTP than wild‐type eIF4E. These mutants of eIF4E may have uses in selectively purifying mRNAs with intact 5′‐ends or in determining how the promyelocytic leukemia protein decreases the affinity of eIF4E for mRNA caps.

Plasma Stromal Cell-Derived Factor 1α/CXCL12 Level Predicts Long-Term Adverse Cardiovascular Outcomes in Patients with Coronary Artery Disease

OBJECTIVEnStromal derived factor-1α/CXCL12 is a chemoattractant responsible for homing of progenitor cells to ischemic tissues. We aimed to investigate the association of plasma CXCL12 with long-term cardiovascular outcomes in patients with coronary artery disease (CAD).nnnMETHODSn785 patients aged: 63xa0±xa012 undergoing coronary angiography were independently enrolled into discovery (Nxa0=xa0186) and replication (Nxa0=xa0599) cohorts. Baseline levels of plasma CXCL12 were measured using Quantikine CXCL12 ELISA assay (R&D systems). Patients were followed for cardiovascular death and/or myocardial infarction (MI) for a mean of 2.6xa0yrs. Cox proportional hazard was used to determine independent predictors of cardiovascular death/MI.nnnRESULTSnThe incidence of cardiovascular death/MI was 13% (Nxa0=xa099). High CXCL12 level based on best discriminatory threshold derived from the ROC analysis predicted risk of cardiovascular death/MI (HRxa0=xa04.81, pxa0=xa01xa0×xa010(-6)) independent of traditional risk factors in the pooled cohort. Addition of CXCL12 to a baseline model was associated with a significant improvement in c-statistic (AUC: 0.67-0.73, pxa0=xa00.03). Addition of CXCL12 was associated with correct risk reclassification of 40% of events and 10.5% of non-events. Similarly for the outcome of cardiovascular death, the addition of the CXCL12 to the baseline model was associated with correct reclassification of 20.7% of events and 9% of non-events. These results were replicated in two independent cohorts.nnnCONCLUSIONnPlasma CXCL12 level is a strong independent predictor of adverse cardiovascular outcomes in patients with CAD and improves risk reclassification.

Whole blood gene expression profiles distinguish clinical phenotypes of venous thromboembolism

INTRODUCTIONnRecurrent venous thromboembolism (VTE) occurs infrequently following a provoked event but occurs in up to 30% of individuals following an initial unprovoked event. There is limited understanding of the biological mechanisms that predispose patients to recurrent VTE.nnnOBJECTIVESnTo identify whole blood gene expression profiles that distinguished patients with clinically distinct patterns of VTE.nnnPATIENTS/METHODSnWe studied 107 patients with VTE separated into 3 groups: (1) low-risk patients had one or more provoked VTE; (2) moderate-risk patients had a single unprovoked VTE; (3) high-risk patients had ≥2 unprovoked VTE. Each patient group was also compared to twenty-five individuals with no personal history of VTE. Total RNA from whole blood was isolated and hybridized to Illumina HT-12V4 Beadchips to assay whole genome expression.nnnRESULTSnUsing class prediction analysis, we distinguished high-risk patients from low-risk patients and healthy controls with good receiver operating curve characteristics (AUC=0.81 and 0.84, respectively). We also distinguished moderate-risk individuals and low-risk individuals from healthy controls with AUCs of 0.69 and 0.80, respectively. Using differential expression analysis, we identified several genes previously implicated in thrombotic disorders by genetic analyses, including SELP, KLKB1, ANXA5, and CD46. Protein levels for several of the identified genes were not significantly different between the different groups.nnnCONCLUSIONnGene expression profiles are capable of distinguishing patients with different clinical presentations of VTE, and genes relevant to VTE risk are frequently differentially expressed in these comparisons.