Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans.

BACKGROUND & AIMS: Mechanisms leading to non-alcoholic steatohepatitis (NASH) have remained unclear, and non-invasive diagnosis of NASH is challenging. In this study, we investigated the benefits of measuring serum interleukin 1 receptor antagonist (IL-1RA) levels. METHODS: Liver biopsies from 119 morbidly obese individuals (47.5 ± 9.0 years, BMI 44.9 ± 5.9 kg/m(2)) were used for histological and gene expression assessment. In a cross-sectional population-based cohort of 6447 men (58 ± 7 years, BMI 27.0 ± 3.9 kg/m(2)) the association of serum IL1-RA with serum alanine aminotransferase (ALT) levels was investigated. RESULTS: Serum levels of IL-1RA, and liver mRNA expression of IL1RN are associated with NASH and the degree of lobular inflammation in liver (p<0.05). The decrease in serum IL-1RA level and expression of IL1RN after obesity surgery correlated with the improvement of lobular inflammation (p<0.05). We developed a novel NAFLD Liver Inflammation Score, including serum Il-1RA concentration, which performed better to diagnose NASH than did previously published scores. Results from the population study confirmed the potential of measuring serum IL-1RA level. The strongest determinants of the ALT concentration at the population level were Matsuda insulin sensitivity index (r(2)=0.130, p=7 × 10(-197)) and serum IL-1RA concentration (r(2)=0.074, p=1 × 10(-110)). IL-1RA concentrations associated significantly with ALT levels even after adjusting for BMI, alcohol consumption and insulin sensitivity (p=2 × 10(-21)). CONCLUSIONS: IL-1RA serum levels associate with liver inflammation and serum ALT independently of obesity, alcohol consumption and insulin resistance, suggesting a potential use of IL-1RA as a non-invasive inflammatory marker for NASH.

Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index.

Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the most prevalent forms of anemia and often occur concurrently. Standard tests of iron status used in differential diagnosis are affected by inflammation, hindering clinical interpretation. In contrast, soluble transferrin receptor (sTfR) indicates iron deficiency and is unaffected by inflammation. Objectives of this prospective multicenter clinical trial were to evaluate and compare the diagnostic accuracy of sTfR and the sTfR/log ferritin index (sTfR Index) for differential diagnosis using the automated Access(®) sTfR assay (Beckman Coulter) and sTfR Index. We consecutively enrolled 145 anemic patients with common disorders associated with IDA and ACD. Subjects with IDA or ACD + IDA had significantly higher sTfR and sTfR Index values than subjects with ACD (P < 0.0001). ROC curves produced the following cutoffs for sTfR: 21 nmol/L (or 1.55 mg/L), and the sTfR Index: 14 (using nmol/L) (or 1.03 using mg/L). The sTfR Index was superior to sTfR (AUC 0.87 vs. 0.74, P < 0.0001). Use of all three parameters in combination more than doubled the detection of IDA, from 41% (ferritin alone) to 92% (ferritin, sTfR, sTfR Index). Use of sTfR and the sTfR Index improves detection of IDA, particularly in situations where routine markers provide equivocal results. Findings demonstrate a significant advantage in the simultaneous determination of ferritin, sTfR and sTfR Index. Obtaining a ferritin level alone may delay diagnosis of combined IDA and ACD.

The activation of the inflammatory cytokines in overweight patients with mild obstructive sleep apnoea.

It is widely accepted that obstructive sleep apnoea (OSA) is linked with cardiovascular diseases. The relationship is complex and remains still poorly understood. The presence of chronic systemic inflammation has been connected with pathogenesis of both OSA and cardiovascular diseases. While atherogenesis is believed to be a process of many years, little is known about the potential impact of the largest OSA subgroup, mild OSA, on the development of cardiovascular diseases. The aim of the present study was to assess whether untreated mild OSA is associated with an activation of inflammatory cytokine system. The adult study population consisted of two groups: 84 patients with mild OSA [apnoea-hypopnoea index (AHI) 5-15 h(-1)] and 40 controls (AHI <5 h(-1)). Serum concentrations of pro- and anti-inflammatory cytokines were measured before any interventions. After adjustments for age, sex, body mass index, fat percentage, most important cardiometabolic and inflammatory diseases, and non-steroidal anti-inflammatory medication, the mean level of tumour necrosis factor-alpha was significantly elevated (1.54 versus 1.17 pg mL(-1), P = 0.004), whereas the level of interleukin-1 beta (IL-1 beta) was reduced (0.19 versus 0.23 pg mL(-1), P = 0.004) in patients with mild OSA compared with controls. The concentrations of the protective anti-inflammatory cytokines, interleukin-10 (1.28 versus 0.70 pg mL(-1), P < 0.001) and interleukin-1 receptor antagonist (478 versus 330 pg mL(-1), P = 0.003) were elevated in the OSA group. The concentrations of C-reactive protein increased, but IL-1 beta decreased along with the increase of AHI. Mild OSA was found to be associated not only with the activation of the pro-inflammatory, but also with the anti-inflammatory systems.

Maternal serum hepcidin is low at term and independent of cord blood iron status.

OBJECTIVES: Hepcidin is the key regulator of iron homeostasis. The aims of this study were to determine serum hepcidin concentrations and reference ranges in pregnant women and cord blood of newborns at term and to evaluate the associations between hepcidin concentrations and iron status parameters. METHODS: A total of 191 pregnant women-newborn pairs were studied in Kuopio University Hospital, Finland. The measured parameters were serum hepcidin, ferritin, transferrin receptor, transferrin saturation, red cell indices, and erythropoietin. RESULTS: The hepcidin concentration in pregnant women was significantly lower than in cord blood at term [geometric mean concentration (GMC) (95% confidence intervals) in pregnant women 10.7 ng/mL (8.5-13.4 ng/mL) vs. GMC of cord blood hepcidin 69.3 ng/mL (55.3-86.8 ng/mL), P<0.001, adjusted analysis of variance]. Hepcidin was undetectable in 12% of mothers. Hepcidin concentration in pregnant women was the lowest in those who had the lowest iron status. However, maternal hepcidin concentration was not associated with cord blood hepcidin or iron status markers. Hepcidin concentration in cord blood was associated with cord blood iron status, but not with maternal iron status. CONCLUSIONS: At term pregnancy, hepcidin concentrations are very low, allowing maximal availability of iron for the fetus. Maternal and cord blood hepcidin levels were independently associated with either maternal or cord blood iron status.

Transferrin receptor expression on reticulocytes as a marker of iron status in dialyzed patients.

BACKGROUND: Erythropoietin therapy should be accompanied by an adequate iron supply in order to avoid functional iron deficiency (FID) related to enhanced erythropoiesis. Therefore, accurate monitoring of the body's iron homeostasis is needed. This study was conducted to investigate whether transferrin receptor (TfR) expression on reticulocytes can reflect iron status in patients with chronic renal failure (CRF). METHODS: TfR expression [antibody binding capacity (ABC)] and the proportion of TfR positive reticulocytes (%TfR+ Ret) relative to all reticulocytes were measured by a quantitative flow cytometric method at baseline and at 3 weeks in 34 dialysis patients. Iron status (plasma ferritin and soluble TfR) and hemoglobin (Hb) with advanced cellular indices, such as the percentage of hypochromic reticulocytes (%HYPOr) and cellular Hb in reticulocytes (CHr), were also analyzed. RESULTS: Patients with FID had significantly higher TfR ABC and %TfR+ Ret compared with patients with replete iron status (p=0.034 and p=0.006, respectively). In patients whose Hb concentrations showed a reduction, the mean increase (3 weeks- baseline) in TfR ABC was four-fold higher and %TfR(+)Ret was three-fold higher when compared with patients whose Hb was stable or had increased. The changes in TfR expression correlated significantly with the changes in reticulocyte indices [CHr (negatively), %HYPOr (positively)] and plasma ferritin (negatively). CONCLUSIONS: Reticulocyte TfR expression reflected the changes in the Hb level and the iron availability at the cellular level, and therefore it might be useful in the assessment of iron status in patients with CRF.

Maternal serum ADMA is not associated with proinflammatory cytokines or C-reactive protein during normal pregnancy.

Normal pregnancy is associated with changes in the immune system. We studied whether asymmetrical dimethylarginine (ADMA) is associated with this immune system change by assaying high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The cytokine and dimethylarginine serum concentrations were determined from women with normal pregnancy (n=77) and healthy non-pregnant controls (n=61) matched for age and smoking status as a part of a large population-based, prospective cohort study conducted in Finland. The hsCRP levels were significantly elevated in the second (P=0.016) and third trimesters (P=0.001) of pregnancy compared to the levels of non-pregnant women. IL-6 levels were significantly higher in the third trimester (P=0.029) of pregnancy than in non-pregnant state. TNF-alpha concentrations did not change significantly during pregnancy. ADMA and SDMA concentrations were significantly lower during pregnancy compared to the levels of non-pregnant women (P<0.001). There was no significant association between ADMA and inflammation markers regardless of the elevated serum concentrations of hsCRP and IL-6 in the third trimester of normal pregnancy. These results suggest that maternal systemic ADMA and SDMA concentrations are more likely to become decreased due to the hemodilution and increased renal clearance than being directly influenced by the change of cytokines during pregnancy.

Early signs of maternal iron deficiency do not influence the iron status of the newborn, but are associated with higher infant birthweight.

OBJECTIVE: To investigate the associations between maternal iron status, pregnancy outcome and newborn iron status using sensitive and specific red blood cell indices reflecting iron-deficient erythropoiesis. DESIGN AND SETTING: Cross-sectional study in Kuopio University Hospital, Finland. POPULATION: One hundred and ninety-two pregnant women and their full-term newborns (cord blood). METHODS: Quartile analysis and Spearman correlations were used to investigate the associations of the iron status of pregnant women with that of their newborns, and with pregnancy outcome. MAIN OUTCOME MEASURES: Maternal and cord blood analysis including indices reflecting the hemoglobin (Hb) content of red blood cells as well as serum iron, transferrin saturation, transferrin receptor and ferritin. Gestational age, birthweight and placental weight. RESULTS: The highest quartile of the maternal percentage of hypochromic red blood cells (%HYPOm) indicating the lowest iron status was associated with a high birthweight and a long duration of pregnancy. The newborns in this group did not show any signs of iron deficiency even though the maternal %HYPOm was elevated. CONCLUSIONS: In a well-nourished maternal population, lower maternal iron status did not affect the iron accumulation on the fetal side. However, longer duration of pregnancy and growth of the fetus appeared to be associated with a lower amount of iron for Hb synthesis in maternal red blood cells, as reflected by the increased maternal %HYPOm, birthweight and length of gestation.

Clinical significance of troponin I efflux and troponin autoantibodies in patients with dilated cardiomyopathy.

BACKGROUND: The appearance of circulating autoantibodies against cardiac troponin I (cTnAbs) in patients with heart failure has been reported. We sought to evaluate the role of circulating cardiac troponin I (cTnI) and cTnAbs in the pathophysiology and prognosis of idiopathic dilated cardiomyopathy. METHODS AND RESULTS: Circulating concentrations of cTnI and the presence of cTnAbs were determined in 95 patients with idiopathic dilated cardiomyopathy. The patients underwent laboratory testing, echocardiography, cardiopulmonary exercise testing, gated single photon emission computed tomography, and both-sided cardiac catheterization during a 3-day study period. Compared with cTnI- patients, the hearts of cTnI+ patients (cTnI > or = 0.01 ng/mL, n = 19) were significantly more dilated (left ventricular end-diastolic diameter 67 vs 61 mm, P < .05; left ventricular end-systolic dimension, 55 vs 49 mm, P < .01; echocardiography) and demonstrated greater intracardiac volumes (left ventricular end-diastolic volume 161 vs 132 mL, P = .060; left ventricular end-systolic volume 112 vs 82 mL, P < .05; gated single photon emission computed tomography), more disturbed systolic (ejection fraction 27 vs 33%, P < .05; gated single photon emission computed tomography) and cardiac sympathetic (123I-metaiodobenzylguanidine washout: 41% vs 34%; P < .05) function, and higher levels of vasoactive peptides (N-terminal proatrial natriuretic peptide 1030 vs 558 pmol/L, P < .05; N-terminal pro-B type natriuretic peptide 337 vs 115 pmol/L, P < .05). In addition, during a median follow-up time of 4.1 years, cTnI+ patients had clinical end points (cardiovascular death, heart transplantation, or clinical need for an automatic implantable cardioverter defibrillator) more often than cTnI- patients (37% vs 8%, P < .01). The presence of circulating cTnAbs (n = 15) was not associated with patients' clinical status or outcome. CONCLUSION: Patients with idiopathic dilated cardiomyopathy with cTnI efflux demonstrate more prominent changes in the indices of left ventricular remodeling and function than patients without signs of cTnI efflux. Moreover, elevated serum cTnI is associated with poor clinical outcome. The presence of circulating cTnAbs seems to have less utility in the clinical assessment of these patients. However, their pathogenic role in disease progression in the long term cannot be excluded.

Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure.

BACKGROUND: Cytokines play an important role in chronic heart failure (HF), but little is known about their involvement in acute decompensated heart failure (ADHF). AIM: To evaluate the prognostic role of inflammatory cytokines in patients with ADHF. METHODS: Levels of interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha), IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured in 423 patients with ADHF. In addition, appropriate cytokine gene polymorphisms were determined. Survival was followed up to 12 months, and prognostic factors were evaluated. RESULTS: Elevated levels of IL-6 and TNF-alpha were strongly associated with increased 12-month mortality (P<0.001 for both), whereas the level of IL-10 was predictive only of 6-month mortality (P<0.01). In multivariate analysis IL-6, chronic renal insufficiency, NT-proBNP, age/10 years' increase and TNF-alpha were identified as the most powerful predictors of 12-month mortality. Furthermore, high levels of both IL-6 and NT-proBNP were associated with >7-fold mortality. Cytokine gene polymorphisms were not associated with outcome. CONCLUSIONS: Circulating levels of pro-inflammatory cytokines IL-6 and TNF-alpha, and the level of an anti-inflammatory cytokine IL-10, but not their gene polymorphisms, provide novel and important prognostic information in patients with ADHF. Combining measurements of pro-inflammatory cytokines and NT-proBNP seems a promising tool in the prognostic assessment of these patients.

Subtle changes in ADMA and l-arginine concentrations in normal pregnancies are unlikely to account for pregnancy-related increased flow-mediated dilatation.

BACKGROUND: Our objective was to investigate whether serum concentrations of asymmetric dimethylarginine (ADMA) or l-arginine correlate to hyperlipidemia or endothelial function in normal pregnancy compared with the non-pregnant subjects. METHODS AND RESULTS: As a part of population-based, prospective cohort Cardiovascular Risk in Young Finns study conducted in Finland we examined 57 pregnant Finnish women throughout gestation and 62 control women matched for age and smoking. Serum glucose, triglycerides (TG), total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C) and ADMA, symmetric dimethylarginine (SDMA) and l-arginine were determined concomitantly with endothelium-dependent brachial artery flow-mediated dilation (FMD), measured by ultrasound. All serum lipid concentrations were significantly higher in pregnant women than in non-pregnant women (P < 0.001 for each). The mean serum ADMA concentration in pregnant women was significantly lower compared with the non-pregnant controls (0.513 micromol l(-1) +/- 0.0593 versus 0.577 micromol l(-1) +/- 0.0710, P < 0.001). Lowered ADMA concentrations did not correlate statistically to FMD in these healthy pregnant women but FMD was enhanced towards the end of pregnancy. CONCLUSIONS: ADMA and l-arginine concentrations fall in normal pregnancy despite marked hypercholesterolemia. Endothelium-dependent vasodilation is enhanced in normal pregnancy but is not statistically correlated to maternal serum ADMA or l-arginine concentrations.

Utility of plasma apelin and other indices of cardiac dysfunction in the clinical assessment of patients with dilated cardiomyopathy.

Apelin is a recently discovered peptide ligand reported to be involved in the regulation of cardiovascular homeostasis. The exact role of apelin in the pathophysiology of congestive heart failure has remained obscure, and the reported circulating levels of apelin in patients with heart failure have been contradictory. To establish the role of apelin in the assessment of cardiac dysfunction we measured plasma apelin levels in 65 patients with congestive heart failure caused by idiopathic dilated cardiomyopathy (IDC) and 14 healthy volunteers by specific radioimmunoassay. IDC patients were carefully examined including echocardiography, both-sided cardiac catheterization and cardiopulmonary exercise test. In addition, plasma levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), N-terminal pro-atrial natriuretic peptide (NT-proANP), interleukin (IL)-6, tumor necrosis factor alpha (TNF-alpha), epinephrine and norepinephrine were determined. Plasma apelin levels were similar in IDC patients (median 26.5 pg/ml, range<3.40-97.6 pg/ml) and in control subjects (median 24.1 pg/ml, range 19.0-28.7 pg/ml; p=NS). Unlike the levels of NT-proBNP, IL-6, TNF-alpha, and norepinephrine, plasma apelin levels did not reflect the severity of heart failure. Our study demonstrates that although disturbed apelin-APJ signalling in heart may play a role in the pathophysiology of heart failure, circulating apelin levels cannot be applied in the clinical assessment of patients with chronic left ventricular dysfunction.

Use of advanced red blood cell and reticulocyte indices improves the accuracy in diagnosing iron deficiency in pregnant women at term.

OBJECTIVES: Detection of iron deficiency during pregnancy with hemoglobin (Hb) and serum measurements is insignificant as the measurements may be affected by e.g. hemodilution or accelerated erythropoiesis. This study tests whether cell indices will give a more reliable measure of iron deficiency in pregnant women at term. METHODS: The population was 202 pregnant women. Using the ADVIA 120 hematology system, Hb, mean cell volume (MCV), percentage of hypochromic red blood cells (%HYPOm) and reticulocytes (%HYPOr), and cellular hemoglobin in reticulocytes (CHr) were tested. Additionally, transferrin saturation (TfSat), ferritin, and transferrin receptor (TfR) were analyzed. Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were used as statistical methods. RESULTS: When TfSat (< or = 11%) was used as the reference test for iron deficiency, %HYPOm and CHr had a sensitivity of 58.1% and 80.7%, while the specificities were 82.6% and 71.3%, respectively. Additionally, the AUC values were %HYPOr 0.80, CHr 0.79, ferritin 0.77, %HYPOm 0.75, TfR 0.67, MCV 0.63 and Hb 0.64. The results provided by the cell indices alone (%HYPOm or CHr) were in good agreement with the results based on the usage of a combination of three commonly used tests (Hb, MCV, ferritin). CONCLUSIONS: This study suggests that the most practical way to diagnose iron deficiency in pregnant women at term is to use cell indices such as CHr and %HYPOm provided by the automated hematological analyzer. Further studies are needed to determine the usefulness of the cell indices in diagnosing iron deficiency longitudinally during the course of pregnancy.

Body iron is a contributor to oxidative damage of DNA.

The transition metal iron is catalytically highly active in vitro, and not surprisingly, body iron has been suggested to promote oxidative stress in vivo. In the current analysis we studied the association of serum ferritin concentration and serum soluble transferrin receptor concentration with daily urinary 8-hydroxydeoxyguanosine excretion, a marker of oxidative stress, in 48 mildly dyslipidemic men in East Finland. In multivariate linear regression analyses allowing for age, smoking, body mass index and physical exercise, serum ferritin concentration predicted the excretion rate at B = 0.17 (95% CI 0.08-0.26, P = 0.001), and serum soluble transferrin receptor to ferritin concentration ratio (TfR/ferritin) predicted the excretion rate at B = - 0.13 (95% CI - 0.21 to - 0.05, P = 0.002). Our data suggest that body iron contributes to excess oxidative stress already at non-iron overload concentrations in these subjects.

Quantitative flow cytometric analysis of transferrin receptor expression on reticulocytes.

BACKGROUND: A quantitative flow cytometric (FCM) method for transferrin receptor (TfR) expression on reticulocytes was developed and the results were compared with the markers of iron status. METHODS: A quantitative FCM analysis was performed using the Quantum Simply Cellular kit, according to which the antibody binding capacity (ABC) of TfR expression on reticulocytes was measured using a monoclonal antibody (CD71). Thiazole orange dye was used to identify reticulocytes. The proportion of TfR positive reticulocytes (%TfR(+)Ret) of all reticulocytes was also analyzed. The population consisted of 46 patients and 12 controls. Patients were categorized (based on Advia 120 cellular indices and serum iron status parameters) as having replete iron status, functional iron deficiency (FID), and as FID combined with depletion of iron stores (FID+ID). RESULTS: The TfR expression (ABC values) were higher in FID (1763+/-922, p<0.001) and FID+ID (1441+/-727, p=0.05) groups in comparison with the controls (663+/-110). Also, the %TfR(+)Rets were significantly higher in iron deficiency states than in controls. CONCLUSIONS: The quantitative FCM method for TfR expression on reticulocytes was found to reflect iron status at the cellular level. The potential usefulness of this method should be evaluated further in larger and more defined study populations.

Changes in inflammatory cytokines are related to impaired glucose tolerance in offspring of type 2 diabetic subjects.

OBJECTIVE: We sought to determine whether levels of inflammatory markers and different cytokines are abnormal in nondiabetic offspring of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Cytokine levels were measured in 19 healthy control subjects and 129 offspring of patients with type 2 diabetes (109 with normal glucose tolerance [NGT] and 20 with impaired glucose tolerance [IGT]). Insulin sensitivity was determined with the hyperinsulinemic-euglycemic clamp, insulin secretion with the intravenous glucose tolerance test, and abdominal fat distribution with computed tomography. RESULTS: Levels of C-reactive protein and inflammatory cytokines were elevated in nondiabetic offspring of type 2 diabetic subjects. Interleukin (IL)-1beta was increased in the NGT group and decreased in the IGT group. In contrast, levels of IL-1 receptor antagonist (IL-1Ra) were increased in both groups. IL-1beta and -Ra levels correlated inversely (P < 0.05) with rates of whole-body glucose uptake and IL-1beta positively with visceral fat mass (P < 0.05) in normoglycemic offspring. CONCLUSIONS: Nondiabetic offspring of type 2 diabetic subjects have changes in the levels of inflammatory cytokines. The level of IL-1Ra seems to be the most sensitive marker of cytokine response in the pre-diabetic state.

Sensitive and quantitative, 10-min immunofluorometric assay for D-Dimer in whole blood.

INTRODUCTION: Normal concentrations of D-Dimer can be used to exclude venous thromboembolism (VTE). However, methods for sensitive and quantitative D-Dimer measurements at the point-of-care (POC) are still limited. MATERIALS AND METHODS: We developed a 10-min, non-competitive immunofluorometric assay for D-Dimer in citrated whole blood and plasma using pre-dispensed reagents dried in single assay wells. The simple, automated assay procedure comprises a 1:50 sample dilution, one-step incubation, washing, and time-resolved fluorometric measurement directly from the wet well surface. RESULTS: The limits of detection (background + 3SD) and quantification (CV <15%) were 0.05 and 0.2 mg/L D-Dimer, respectively, and the assay was linear up to 400 mg/L. Correlations to Roche TinaQuant (r=0.726, n=200) and Biopool Auto.Dimer (r=0.190, n=149) were carried out using citrated plasma. Diagnostic sensitivity, specificity, and negative (NPV) and positive (PPV) predictive values were 98.7%, 64.4%, 99.1% and 55.1%, and 92.2%, 81.0%, 95.9% and 68.3%, respectively, using cut-off values of 0.6 and 1.0 mg/L, respectively, in outpatients with deep vein thrombosis (DVT) and/or pulmonary embolism (PE) (n=77) compared with outpatients with various other diseases (n=174). The within- and between-run CVs near the cut-off values were < or =10% in both whole blood and plasma. The 95th percentile upper range in apparently healthy individuals was 0.68 mg/L of whole blood (n=101). CONCLUSIONS: The high sensitivity and NPV suggest that the rapid immunofluorometric assay could be valuable for rapid exclusion of VTE in outpatients. With appropriate cut-offs, the assay could potentially be used as a stand-alone test or combined with clinical probability assessment, but further studies are required.

MTHFR C677T polymorphism is not associated with placental abruption or preeclampsia in Finnish women.

OBJECTIVE: The aim of our study was to examine genetic variability in the gene encoding methylenetetrahydrofolate reductase (MTHFR) and individual susceptibility to the placental abruption or preeclampsia. METHODS: 362 women (133 with preeclampsia, 117 with placental abruption, and 112 healthy controls) were genotyped for C677T polymorphism in the MTHFR gene. RESULTS: Similar genotype distributions were observed in the frequencies of C/C homozygotes (58.6%, 64.1%, and 57.1% for the three groups, respectively) and mutant homozygotes T/T (9.0%, 5.1% and 5.4%). No significant differences were detected in T allele frequencies (25.2%, 20.5%, and 24.1% for the three groups, respectively). CONCLUSIONS: MTHFR C677T polymorphism does not have a major role in the development of preeclampsia or placental abruption in the Finnish population.

Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome.

BACKGROUND: Detailed metabolic defects in glucose and energy metabolism and abnormalities in a variety of cardiovascular risk factors are largely unknown in subjects with the metabolic syndrome. METHODS AND RESULTS: We characterized the metabolic syndrome in 119 nondiabetic offspring of diabetic probands. Cardiovascular risk factors, including cytokines and adhesion molecules, were measured. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp and indirect calorimetry; intra-abdominal fat and subcutaneous fat were assessed by CT; and maximal oxygen consumption was measured with a bicycle ergometer test. By applying factor analysis, we identified a single factor, the metabolic syndrome factor, from the following variables: 2-hour glucose, fasting insulin, body mass index, waist, HDL cholesterol, triglycerides, and mean blood pressure. Subjects with the highest factor score were defined as having the metabolic syndrome. During hyperinsulinemia, the highest factor score was associated with decreased rates of glucose oxidation and nonoxidative glucose disposal, high rates of lipid oxidation, low energy expenditure, and impaired suppression of free fatty acids during hyperinsulinemia. Furthermore, the metabolic syndrome was associated with a high amount of visceral fat, hypoadiponectinemia, a low maximum oxygen uptake, and high levels of C-reactive protein, proinflammatory cytokines, and adhesion molecules. CONCLUSIONS: The metabolic syndrome is characterized by an excess of intra-abdominal fat, hypoadiponectinemia, insulin resistance in skeletal muscle and adipose tissue, multiple defects in glucose and energy metabolism, and elevated levels of cytokines and adhesion molecules.