Outperformance of interleukin-6 over placental alpha microglobulin-1 in predicting preterm delivery in symptomatic women.

BACKGROUND: Threatened preterm labor is the major cause of hospital admission during the second half of pregnancy. An early diagnosis is crucial for adopting pharmacologic measures to reduce perinatal mortality and morbidity. Current diagnostic criteria are based on symptoms and short cervical length. However, there is a high false-positive rate when using these criteria, which implies overtreatment, causing unnecessary side effects and an avoidable economic burden. OBJECTIVE: This study aimed to compare the use of placental alpha microglobulin-1 and interleukin-6 as vaginal biomarkers combined with cervical length and other maternal characteristics to improve the prediction of preterm delivery in symptomatic women. STUDY DESIGN: A prospective observational study was conducted in women with singleton pregnancies complicated by threatened preterm labor with intact membranes at 24+0 to 34+6 weeks of gestation. A total of 136 women were included in this study. Vaginal fluid was collected with a swab for placental alpha microglobulin-1 determination using the PartoSure test, interleukin-6 was assessed by electrochemiluminescence immunoassay, cervical length was measured by transvaginal ultrasound, and obstetrical variables and newborn details were retrieved from clinical records. These characteristics were used to fit univariate binary logistic regression models to predict time to delivery <7 days, time to delivery <14 days, gestational age at delivery ≤34 weeks, and gestational age at delivery ≤37 weeks, and multivariate binary logistic regression models were fitted with imbalanced and balanced data. Performance of models was assessed by their F2-scores and other metrics, and the association of their variables with a risk or a protective factor was studied. RESULTS: A total of 136 women were recruited, of whom 8 were lost to follow-up and 7 were excluded. Of the remaining 121 patients, 22 had a time to delivery <7 days and 31 had a time to delivery <14 days, and 30 deliveries occurred with a gestational age at delivery ≤34 weeks and 55 with a gestational age at delivery ≤37 weeks. Univariate binary logistic regression models fitted with the log transformation of interleukin-6 showed the greatest F2-scores in most studies, which outperformed those of models fitted with placental alpha microglobulin-1 (log[interleukin-6] vs placental alpha microglobulin-1 in time to delivery <7 days: 0.38 vs 0.30; time to delivery <14 days: 0.58 vs 0.29; gestational age at delivery ≤34 weeks: 0.56 vs 0.29; gestational age at delivery ≤37 weeks: 0.61 vs 0.16). Multivariate logistic regression models fitted with imbalanced data sets outperformed most univariate models (F2-score in time to delivery <7 days: 0.63; time to delivery <14 days: 0.54; gestational age at delivery ≤34 weeks: 0.62; gestational age at delivery ≤37 weeks: 0.73). The performance of prediction of multivariate models was drastically improved when data sets were balanced, and was maximum for time to delivery <7 days (F2-score: 0.88±0.2; positive predictive value: 0.86±0.02; negative predictive value: 0.89±0.03). CONCLUSION: A multivariate assessment including interleukin-6 may lead to more targeted treatment, thus reducing unnecessary hospitalization and avoiding unnecessary maternal-fetal treatment.

A more accurate prediction to rule in and rule out pre-eclampsia using the sFlt-1/PlGF ratio and NT-proBNP as biomarkers.

Background The management of potential pre-eclamptic patients using the soluble FMS-like tyrosine kinase 1 (sFlt-1)/ placental growth factor (PlGF) ratio is characterised by frequent false-positive results. Methods A retrospective cohort study was conducted to identify and validate cut-off values, obtained using a machine learning model, for the sFlt-1/PlGF ratio and NT-proBNP that would be predictive of the absence or presence of early-onset pre-eclampsia (PE) in singleton pregnancies presenting at 24 to 33 + 6 weeks of gestation. Results For the development cohort, we defined two sFlt-1/PlGF ratio cut-off values of 23 and 45 to rule out and rule in early-onset PE at any time between 24 and 33 + 6 weeks of gestation. Using an sFlt-1/PlGF ratio cut-off value of 23, the negative predictive value (NPV) for the development of early-onset PE was 100% (95% confidence interval [CI]: 99.5-100). The positive predictive value (PPV) of an sFlt-1/PlGF ratio >45 for a diagnosis of early-onset PE was 49.5% (95% CI: 45.8-55.6). When an NT-proBNP value >174 was combined with an sFlt-1/PlGF ratio >45, the PPV was 86% (95% CI: 79.2-92.6). In the validation cohort, the negative and positive values were very similar to those found for the development cohort. Conclusions An sFlt-1/PlGF ratio <23 rules out early-onset PE between 24 and 33 + 6 weeks of gestation at any time, with an NPV of 100%. An sFlt-1/PlGF ratio >45 with an NT-proBNP value >174 significantly enhances the probability of developing early-onset PE.

Metabolic disorders and inflammation are associated with familial combined hyperlipemia.

BACKGROUND: Familial Combined Hyperlipidemia (FCH) is related to different metabolic disorders. The objective of this study was to evaluate the presence of alterations of hydrocarbonated metabolism and lipid profile together with inflammatory and adhesion molecules in subjects with FCH compared to controls. METHODS: 75 HFC patients and 75 healthy individuals were studied. Glucose, insulin, HOMA-IR index and lipid parameters, in addition to anti-oxidized LDL antibodies (Anti ox-LDL), small and dense LDL (sdLDL) and HDL subfractions, proinflammatory cytokines and adhesion molecules were measured. RESULTS: FCH patients showed higher levels of hydrocarbonated metabolism parameters, total cholesterol, triglycerides, LDLc, Apolipoprotein B and non-HDLc (p < .001), and lower levels of HDLc (p < .001) and Apolipoprotein AI (p < .05) than controls. In addition, the inflammatory markers hsCRP, IL-6, IL-8, P-selectin, E-selectin and ICAM were all higher with (p < .05) respect to controls. The increase of sdLDL was correlated with the presence of IR and IL-6 levels. Significant differences in diameter and percentage of phenotype B LDL, small HDL subfractions and Anti ox-LDL were also detected between patients and controls. CONCLUSIONS: The lipid characteristics of FCH are confirmed by IR and a low grade inflammatory state in patients, and are associated with the predominance of sdLDL and Anti ox-LDL.

Influence of temperature, serum, and gonadotropin supplementation in short- and long-term organotypic culture of human immature testicular tissue.

OBJECTIVE: To study how temperature, serum, and gonadotropin supplementation affect the organotypic culture of human immature testicular tissue (ITT) in vitro. DESIGN: Experimental basic science study. SETTING: Reproductive biology laboratory. PATIENT(S): ITT from 4 boys with cancer that had testicular tissue cryopreserved as part of their fertility preservation treatment. INTERVENTION(S): In vitro organotypic culture of ITT, exposed to different temperatures (37°C vs. 34°C), serum (fetal bovine serum [FBS] vs. Knockout Serum Replacement [KOS]), and gonadotropin supplementation (with and without FSH and LH). MAIN OUTCOME MEASURE(S): Characterization of the tissue was performed at days 0, 14, and 70 with the use of reverse-transcription quantitative polymerase chain reaction, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling, histologic analysis by means of hematoxylin-eosin staining, and immunohistochemical staining. Hormonal secretion was determined at days 3, 14, 28, and 70 by means of immunofluorescent assay. RESULT(S): The 37°C conditions showed an accelerated loss of tubular morphology and higher intratubular apoptosis. KOS supplementation triggered the up-regulation of STAR, SOX9, DAZL, DDX4, PLZF, and UTF1, the percentage of SOX9+/androgen receptor (AR)-positive mature Sertoli cells at day 14, and testosterone secretion. Gonadotropin supplementation increased the numbers of both undifferentiated UTF1+ spermatogonia and premeiotic VASA+/SYCP3+ spermatogonia at day 14, and the number of SOX9+ Sertoli cells at day 70. The low SOX9+/AR+ colocalization, the disorganized pattern of ZO-1, and the progressive decrease of antimüllerian hormone secretion indicated inefficient Sertoli cell maturation in vitro. CONCLUSION(S): The 34°C condition in KOS showed the best results for the survival of both spermatogonia and Sertoli cells. FSH/LH supplementation also improved long-term survival of Sertoli cells and the maturation of spermatogonia up to meiotic initiation in short-term culture.

Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome.

BACKGROUND & AIMS: Phytosterols (PS) lower LDLc, but their effect on metabolic syndrome (MetS) remains unknown. We evaluated whether low-fat milk enriched with PS improves cardiovascular risk factors in these patients. METHODS: A randomised parallel trial employing 24 moderate-hypercholesterolaemic MetS patients and consisting of two 3-month intervention phases. After a 3-month healthy diet, patients were divided into two intervention groups: diet (n = 10) and diet + PS (n = 14) (2 g/day). A control group of 24 moderate-hypercholesterolaemic patients without MetS (matched in age and BMI) underwent the same procedure. RESULTS: Neither dietary intervention nor enrichment of PS induced any improvement in the serum lipoprotein profile of MetS patients. By contrast, in the non-MetS population, a healthy diet effectively reduced TC, LDLc, non-HDLc and Apo B-100, with further decreases in TC (6.9%), LDLc (10.5%), non-HDLc (10.3%), Apo B-100 (6.2%) and Apo B-100/ApoA-I ratio (11.6%) being observed when PS were administered. No differences in LDL diameter, hsCRP or homocysteine were detected in any of the groups after consuming PS. This supplementation produced a significant increase in PS levels only in the non-MetS population. CONCLUSIONS: PS therapy appears to be of little value to MetS patients, likely due to its reduced intestinal cholesterol absorption. The efficacy of PS as hypocholesterolaemic agents is thus limited.

The metabolic syndrome and its individual components: its association with venous thromboembolism in a Mediterranean population.

INTRODUCTION: The association of metabolic syndrome with venous thromboembolism (VTE) remains uncertain. Moreover, the relevance of abdominal obesity as an independent or related risk factor for VTE in the metabolic syndrome cluster is controversial. We aimed to evaluate the impact of metabolic syndrome and its individual components on VTE risk. METHODS: We conducted a case-control study to investigate the presence of metaoblic syndrome in 150 healthy individuals (43 ± 13 years) and 146 patients with a first objectively confirmed episode of deep venous thrombosis or pulmonary embolism (44 ± 13 years) who underwent a thrombophilia work up. RESULTS: Metabolic syndrome was present in 19% of cases and 8% of controls (P = 0.008). In the unadjusted analysis, metabolic syndrome was statistically associated with higher VTE risk [odds ratio (OR) = 2.7, 95% confidence interval (CI) 1.3-5.6]. However, hypertriglyceridemia (OR = 2.0, 95% CI 1.1-3.5), high glucose levels (OR = 2.0, 95% CI 1.2-3.5), and abdominal obesity (OR = 5.7, 95% CI 3.4-9.6) were also significantly associated with higher VTE risk. Abdominal obesity was the factor that had the highest OR. Moreover, after multivariate analysis in which each independent factor was adjusted for the others, only abdominal obesity remained statistically associated with higher VTE risk, revealing its relevance. Further adjustment for the presence of thrombophilia did not change the estimation. CONCLUSION: We conclude that, in subjects with a mean age of 44 years, metabolic syndrome increases VTE risk, although abdominal obesity is the pivotal factor.

Effects of phytosterol ester-enriched low-fat milk on serum lipoprotein profile in mildly hypercholesterolaemic patients are not related to dietary cholesterol or saturated fat intake.

Phytosterols (PS) are recommended to reduce LDL-cholesterol. However, the influence of cholesterol and fat intake on the lipid-lowering effect of PS in mildly hypercholesterolaemia is unclear. Thus, the aim of the present study was to evaluate whether the efficacy of PS is related to the composition of saturated fat and dietary cholesterol intake. Additionally, serum carotenoid content was analysed to evaluate to what extent it was undermined by PS. This was a 3-month randomised, parallel trial with a three-arm design. Patients were divided into three groups: healthy diet (n 24), healthy diet+PS (n 31) and free diet+PS (n 29), receiving 2 g/d of PS. Healthy and free diets were characterised by a daily ingestion of 6.8 % of saturated fat and 194.4 mg of cholesterol and 12.7 % of saturated fat and 268.1 mg of cholesterol, respectively. After PS therapy, patients receiving the healthy diet+PS or a free diet+PS exhibited a similar reduction in total cholesterol (6.7 and 5.5 %), LDL-cholesterol (9.6 and 7.0 %), non-HDL-cholesterol (12.2 and 8.9 %) and apo B-100/apo A-I ratio (11.5 and 11.6 %), respectively. In patients following the healthy diet, (ß-carotene concentration rose by 26.9 %, whereas the ß-carotene and lycopene levels dropped by 21.0 and 22.8 % in the group receiving the free diet+PS, respectively. No change was observed in carotenoid levels in healthy diet+PS group. In conclusion, the efficacy of PS in relation to lipoprotein profile is not influenced by saturated fat or dietary cholesterol intake, which confirms the positive effect of healthy diet therapy in improving the negative effects that PS exert on carotenoid levels.

Evaluation of cardiovascular risk and oxidative stress parameters in hypercholesterolemic subjects on a standard healthy diet including low-fat milk enriched with plant sterols.

A healthy diet and plant sterols (PS) are recommended for reducing low-density lipoprotein (LDL) cholesterol and, subsequently, the risk of premature cardiovascular disease. PS mediate a decrease in fat-soluble vitamin concentration, which can lead to a general impairment of antioxidative defenses and an increase in oxidative stress. Thus, we evaluated the effects of a healthy diet, including PS-enriched low-fat milk, on cardiovascular risk and oxidative stress parameters in hypercholesterolemic subjects. This was a randomized parallel trial employing 40 subjects and consisting of two 3-month intervention phases. After 3 months on a standard healthy diet, subjects were divided into two intervention groups: a diet group and a diet+PS group (2 g/day). Lipid profile, apolipoproteins, high-sensitivity C-reactive protein and oxidative stress parameters were analyzed. Diet significantly reduced total and LDL cholesterol (4.0% and 4.7%, respectively), produced an increase in the level of beta-carotene (23%) and improved the antioxidant capacity of LDL cholesterol particles (4.6%). PS induced a significant decrease in total cholesterol (6.4%), LDL (9.9%) and the apolipoprotein B100/apolipoprotein A1 ratio (4.9%), but led to a decrease in cryptoxanthin level (29%) without any change being observed in the antioxidant capacity of LDL cholesterol particles, total antioxidant status or lipid peroxidation. After 3 months, we observed the positive effect of including a PS supplement in dietary measures, as the lipoprotein-mediated risk of cardiovascular disease was reduced. Despite a decrease in the concentration of cryptoxanthin, no evidence of a global impairment of antioxidative defenses or an enhancement of oxidative stress parameters was found.

Small and dense LDL in familial combined hyperlipidemia and N291S polymorphism of the lipoprotein lipase gene.

There is a predominance of small and dense LDL cholesterol particles in familial combined hyperlipidemia (FCH). The lipoprotein lipase gene could exert an influence in these circumstances.To study the relationship of pattern B LDL and lipids with N291S polymorphism of lipoprotein lipase (LPL) in FCH patients.Lipid profile, apolipoproteins, diameter of LDL and N291S polymorphism were determined in 93 patients with FCH and 286 individuals from the general population.FCH patients with N291S polymorphism showed a lower mean diameter of LDL. FCH patients with pattern B LDL showed higher concentrations of triglycerides, VLDLc, non-HDLc and apo B100 and lower levels of HDLc than those with pattern A. Of FCH patients with polymorphism 87.5% presented pattern B and 12.5% pattern A, while patients without polymorphism presented pattern A in 69.2% cases and pattern B in 30.8% cases, with differences being statistically significant (p < 0.004). The prevalence of this mutation in our FCH patients was 9.7%.The prevalence of N291S mutation in our FCH patients was similar to the 9.3% described in Dutch FCHL patients but clearly higher than the 2-5% described for other Caucasian populations. No polymorphism was found in our general population sample. FCH patients with phenotype B of LDL possessed an atherogenic lipid profile. The relationship between small and dense LDL and the presence of the N291S mutation may identify patients with high cardiovascular risk.

[Metabolic syndrome in patients with coronary heart disease. Results of using different diagnostic criteria]. / Síndrome metabólico en pacientes con cardiopatía isquémica. Resultados obtenidos con la utilización de diferentes criterios.

A unified definition of metabolic syndrome, considered a common feature of cardiovascular risk, is lacking. The aim of this study was to compare the prevalence of this syndrome in patients with ischemic heart disease using two diagnostic criteria: the European Group of Resistance to Insulin and the National Cholesterol Education Program. We designed an observational, cross-sectional study of the factors that make up metabolic syndrome in subjects diagnosed with coronary heart disease. A total of 169 patients aged 35 to 79 years were studied (129 men and 40 women). With the European group criterion the percentage of patients with metabolic syndrome was 43.7%, whereas the American group criterion yielded a prevalence of 40.8% (no significant difference). The prevalence of metabolic syndrome among patients with ischemic heart disease is high. The diagnostic criteria used are similar and do not differ significantly, although diagnostic concordance was only 50%.