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Objective: To evaluate the clinical significance of the combination of cancer antigen-125 (CA-125), human epididymis protein 4 (HE4), and progesterone for the identification of ovarian masses in patients with suspected early stage ovarian cancer (OC)., Materials and Methods: This was a case-control, single-center study of 225 women with a pelvic mass of suspected ovarian origin, including 75 patients with Stage I/II OC and 150 controls. Diagnostic procedures included pelvic and rectal examinations, transvaginal ultrasound, evaluation of CA-125 and HE4 levels alone and in the Risk of Ovarian Malignancy Algorithm (ROMA), and a new algorithm combining ROMA and progesterone., Results: Median CA-125 and HE4 levels were significantly higher in patients with OC compared with women with benign ovarian tumors, irrespective of menopausal status. The highest median progesterone levels occurred in premenopausal women with benign ovarian tumors, compared with premenopausal women with OC with or without benign ovarian disease. The combination of ROMA and progesterone was significantly more accurate at detecting OC compared with ROMA or CA-125 or HE4 alone, but only in premenopausal patients., Conclusion: Different algorithms should be used for diagnosing OC, and the addition of progesterone might improve the performance of ROMA for the diagnosis of pelvic masses in premenopausal women., (Copyright © 2015. Published by Elsevier B.V.)

Aims: We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation., Methods and Results: We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants (n=2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998-2001. The cohort was divided into never (n=1149), former (n=1424), and current smokers with last cigarette >6h (n=134) or < or =6h (n=237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p<0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L (p<0.0001) and higher concentrations of (CRP) C-reactive protein (p=0.002)., Conclusions: As opposed to never smokers, those with acute cigarette smoke exposure (< or =6h) had significantly higher concentrations of all markers (p<0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state.

Background: The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking., Methods: Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function., Results: IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories., Conclusions: Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.

Background: P-selectin is a cell adhesion molecule that is involved in atherogenesis, and soluble concentrations of this biomarker reflect cardiovascular risk. However, the clinical correlates and genetic characterization of soluble P-selectin have not been clearly elucidated., Objective: To describe clinical and genetic correlates of circulating P-selectin in the community., Methods: In Framingham Heart Study Offspring (European descent) and Omni (ethnic/racial minority) participants, we examined the association of cardiovascular risk factors with soluble P-selectin concentrations. In Offspring participants, we evaluated heritability, linkage and association of 29 SELP single-nucleotide polymorphisms (SNPs) with adjusted P-selectin concentrations., Results: In multivariable analysis of 3,690 participants (54% women, mean age 60 +/- 10 years), higher log-transformed P-selectin concentrations were inversely associated with female sex and hormone replacement therapy, and positively associated with age, ethnic/racial minority status, cigarette smoking, waist circumference, systolic blood pressure, fasting glucose, and total/high-density lipoprotein cholesterol and triglyceride concentrations. Clinical factors explained 10.4% of the interindividual variability in P-selectin concentrations. In 571 extended pedigrees (n = 1,841) with >or= 2 phenotyped members per family, multivariable-adjusted heritability was 45.4 +/- 5.8%. Among the SELP SNPs examined, a non-synonymous SNP (rs6136) encoding a threonine-to-proline substitution at position 715 was highly significantly associated with decreased P-selectin concentrations (P = 5.2 x 10(-39)), explaining 9.7% of variation after adjustment for clinical factors., Conclusions: Multiple clinical factors and an SNP in the SELP gene were significantly associated with circulating P-selectin concentrations. One SNP in SELP explained significant variation in circulating P-selectin concentrations, even after accounting for known clinical correlates.

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan. We computed p-values by a permutation approach. Heritability estimates ranged from 14% (IL-6) to 44% (MCP-1) after log transforming and adjusting for covariates. Significant linkage to MCP-1 was found on chromosome 1 (LOD=4.27 at 186cM; genome-wide p=0.005), in a region containing inflammatory candidate genes such as SELE, SELP (E- and P-selectin) and CRP. Other linkage peaks with LOD scores >2 were found for MCP-1 on chromosome 1 (LOD=2.04 at 16cM; LOD=2.34 at 70cM) and chromosome 17 (LOD=2.44 at 22cM) and for sICAM-1 on chromosome 1 at 229cM (LOD=2.09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD.

Objectives: To determine whether prior thromboembolic events (TE) influence current measures of hemostasis, inflammation and oxidative stress in a population at high cardiovascular risk., Background: Renal failure patients demonstrate a remarkably elevated incidence of TE., Methods: Relationships between plasma test results and prior TE history were studied in 78 diabetic and 23 non-diabetic patients with renal failure. TE were defined as myocardial infarction, stroke or vascular surgery., Results: Markers for inflammation (interleukin (IL)-6, C reactive protein (CRP)), thrombosis (fibrinogen, low molecular weight (LMW) fibrinogen, factor VII, viscosity), fibrinolysis (fibrinolytic activity, plasminogen activator inhibitor (PAI)), endothelial/platelet activity (P-selectin, von Willebrand factor (vWf)) and oxidative stress (antibody to oxidized low-density lipoprotein (LDL), advanced glycated end products) were significantly different from a healthy control population. Dialysis patients with diabetes were twice as likely to have sustained a TE (58 vs. 30%, p = 0.032). Those patients in the total group with levels above the median for IL-6 (p = 0.045), and CRP (p < 0.017) were more likely to have sustained a TE than those with levels below the median. Those diabetic patients with levels above the median for CRP were more likely to have a prior history of TE (p < 0.021). For non-diabetic patients, levels above the median of IL-6 were associated with a prior history of TE (p = 0.027). Multiple correlations for factors of inflammation, hemostasis and oxidative stress indicate that these mechanisms are not independent of one another., Conclusion: Prior TE was associated with markers of inflammation a relationship that may influence the interpretation of these tests which are strongly interrelated in patients at high cardiovascular risk.

The present study demonstrates that the fibrinolytic activity is significantly increased and the level of plasminogen antiactivator diminished in the blood of patients with advanced liver cirrhosis and chronic aggressive hepatitis as compared with the values for healthy subjects. Total fibrinogen concentration was similar in patients and controls. However, electrophoresis of plasma with the use of SDS-polyacrylamide gel (3.5%) showed considerable differences in the composition of fibrinogen fractions. Lower molecular weight (LMW and LMW1) clottable protein was significantly (p less than 0.01) increased in the patients. In two out of 22 patients the higher molecular weight (HMW) fraction was virtually absent. In vitro incubation (37 degrees C for 48 hr) of diluted (1:10) plasma from a patient resulted in extensive degradation of a low-solubility fibrinogen fraction (HMW) previously added to the sample. No degradation was observed in any undiluted plasma samples. It is concluded that the increased concentration of lower-molecular-weight forms of clottable protein in the blood of patients with liver disease is probably related to increased in vivo degradation rather than abnormal synthesis. An association rather than a direct correlation with fibrinolytic activity was found.