Background-In patients with established ischemic heart disease, prospective cohort studies have indicated that plasminogen activator inhibitor (PAI-1), the inhibitor of the fibrinolytic system, may predict cardiovascular events. So far, there have been no primary prospective studies of PAI-1. Methods and Results-The aim of the present study was to test whether plasma levels of PAI-1, tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), and thrombomodulin (TM) could predict the occurrence of a first acute myocardial infarction (AMI) in a population with high prevalence of coronary heart disease by use of a prospective nested case-control design. Mass concentrations of PAI-1 and tPA were significantly higher for the 78 subjects who developed a first AMI compared with the 156 references matched for age, sex, and sampling time; for tPA, this increase was independent of smoking habits, body mass index, hypertension, diabetes, cholesterol, and apolipoprotein A-I. The ratio of quartile 4 to 1 for tPA was 5.9 for a patient to develop a first AMI. The association between tPA and AMI was seen in both men and women. Increased levels of vWF were associated with AMI in a univariate analysis. High levels of TM were associated with AMI in women but not in men. Conclusions-The plasma levels of PAI-1, tPA, and vWF are associated with subsequent development of a first AMI; for PAI-1 and tPA, this relation was found in both men and women. For tPA but not for PAI-1 and vWF, this association is independent of established risk factors. (Circulation. 1998;98:2241-2247.)

BackgroundDNA epigenetic modifications, such as methylation, are important regulators of tissue differentiation, contributing to processes of both development and cancer. Profiling the tissue-specific DNA methylome patterns will provide novel insights into normal and pathogenic mechanisms, as well as help in future epigenetic therapies. In this study, 17 somatic tissues from four autopsied humans were subjected to functional genome analysis using the Illumina Infinium HumanMethylation450 BeadChip, covering 486 428 CpG sites.ResultsOnly 2% of the CpGs analyzed are hypermethylated in all 17 tissue specimens; these permanently methylated CpG sites are located predominantly in gene-body regions. In contrast, 15% of the CpGs are hypomethylated in all specimens and are primarily located in regions proximal to transcription start sites. A vast number of tissue-specific differentially methylated regions are identified and considered likely mediators of tissue-specific gene regulatory mechanisms since the hypomethylated regions are closely related to known functions of the corresponding tissue. Finally, a clear inverse correlation is observed between promoter methylation within CpG islands and gene expression data obtained from publicly available databases.ConclusionsThis genome-wide methylation profiling study identified tissue-specific differentially methylated regions in 17 human somatic tissues. Many of the genes corresponding to these differentially methylated regions contribute to tissue-specific functions. Future studies may use these data as a reference to identify markers of perturbed differentiation and disease-related pathogenic mechanisms.

Background and Purpose —Abnormalities in the fibrinolytic system have been associated with an increased risk for stroke in a few studies. This study was designed to test whether plasma levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and tPA/PAI-1 complex could predict a first-ever stroke. Methods —The study was an incident case-control study nested within the Västerbotten Intervention Program and the Northern Sweden Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) cohorts. In this study 108 first-ever stroke cases were defined according to the MONICA classification, and 216 controls from the same cohort were randomly selected and matched for age, sex, sampling time, and geographic region. Results —Stroke occurred on average 30 months after the blood sampling date. The mean plasma concentration of tPA/PAI-1 complex was higher for the stroke cases than for the controls (3.9 versus 3.0 μg/L). In univariate regression analysis, significantly higher odds ratios were found for the tPA/PAI-1 complex as continuous variable. When divided into quartiles, the odds ratio was 2.74 for the highest quartile compared with the lowest. In the multivariate model, the tPA/PAI-1 complex remained an independent predictor for stroke. Additionally, tPA mass concentration quartiles 3 and 4 showed a significant association with all stroke as outcome. No association was found, however, for PAI-1. In subgroup analysis of cerebral hemorrhage (n=18), the mean tPA/PAI-1 complex level was higher for the cases than for the controls (4.8 versus 3.0 μg/L), and in multivariate analysis including all controls (n=216), only tPA/PAI-1 complex remained significant. Conclusions —This prospective study shows that tPA/PAI-1 complex, a novel fibrinolytic marker, is independently associated with the development of a first-ever stroke, especially hemorrhagic stroke. This finding supports the hypothesis that disturbances in fibrinolysis precede a cerebrovascular event.

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Among traditional risk factors for atherosclerosis, some were associated with AAA and others were not, indicating complex and partly different causes. Inflammation and heredity appear to be important factors in the development of AAA.

An increased mass concentration of t-PA is a new risk factor of long-term mortality in patients with angina pectoris and coronary artery stenosis. This paradoxical effect probably reflects increased t-PA levels attributable to enzyme inhibitor complex formation in subjects with increased plasma levels of t-PA inhibitors.

This review summarizes current knowledge of the effect of folate-mediated one-carbon metabolism and related genetic variants on female fertility and pregnancy viability. Insufficient folate status disrupts DNA methylation and integrity and increases blood homocysteine levels. Elevated levels of follicular fluid homocysteine correlate with oocyte immaturity and poor early embryo quality, while methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with lower ovarian reserves, diminished response to follicular stimulation, and reduced chance of live birth after in vitro fertilization. Embryos carrying multiple MTHFR variants appear to have a selective disadvantage; however, the heterozygous MTHFR 677CT genotype in the mother and fetus provides the greatest chance for a viable pregnancy and live birth, possibly due to a favorable balance in folate cofactor distribution between methyl donor and nucleotide synthesis. The results of previous studies clearly emphasize that imbalances in folate metabolism and related gene variants may impair female fecundity as well as compromise implantation and the chance of a live birth.

Clinical diagnosis of acute mesenteric ischemia is difficult. The aim of this review is to provide current status on the search for an accurate plasma biomarker for acute mesenteric ischemia. A search using the medical subject heading terms marker and mesenteric ischemia or intestinal ischemia or superior mesenteric artery occlusion or mesenteric venous thrombosis in the Medline and Embase databases from 1980 to 2011. Studies without a control group or a control group consisted of healthy individuals (human studies), or studies on intestinal reperfusion were excluded. Twenty animal and twelve human studies were identified. In human studies, the studied series of patients had a control group that had a need of laparotomy (n = 2), suspected acute mesenteric ischemia (n = 7), acute abdomen (n = 2) or systemic inflammatory response syndrome (n = 1). D: -dimer has been found to be the most consistent highly sensitive early marker, but specificity was low. The follow-up study on α-glutathione S-transferase yielded inferior sensitivity and accuracy than the preliminary study, clearly questioning the value of this marker. Intestinal fatty acid binding globulin (I-FABP) and D: -lactate are both interesting markers, but the results were conflicting. Different cut-off levels have been used in the studies on I-FABP. The encouraging preliminary result of cobalt-albumin and urinary FABP as an accurate marker needs to be addressed in other study populations. The early clinical and laboratory diagnosis of intestinal ischemia remains a challenge. None of the proposed plasma-derived tests for acute mesenteric ischemia has as yet entered routine clinical practice. The proposed biomarkers need to be evaluated in a prospective clinical research project in patients with acute abdomen.