Significance of Low Maternal Serum Β-hCG Levels in the Assessment of the Risk of Atypical Chromosomal Abnormalities.

INTRODUCTION: The introduction of prenatal cell-free DNA as a screening test has surpassed traditional combined first-trimester screening (cFTS) in the detection of common trisomies. However, its current limitation in detecting only common trisomies is affecting the diagnostic yield for other clinically significant chromosomal abnormalities. METHODS: In efforts to optimize the detection of fetuses with genetic abnormalities, we have analyzed the relationship between the cFTS risk score and biomarkers with atypical chromosomal abnormalities. Furthermore, we have evaluated the impact of prenatal cell-free DNA screening on the detection of chromosomal abnormalities in our population. For these purposes, we performed a retrospective study of 877 singleton pregnancies who underwent chromosomal microarray analysis (CMA) between 2013 and 2020 and for whom cFTS data were available. RESULTS: The results demonstrated that low levels of free beta-human chorionic gonadotropin (ß-hCG) (≤0.37 multiples of the median) and increased fetal nuchal translucency (NT) (≥3.5 mm) were statistically associated with the presence of atypical chromosomal abnormalities. In fact, the risk of pathogenic CMA results increased from 6 to 10% when fetal NT was increased and from 6 to 20% when a low serum ß-hCG level was detected in the high-risk cFTS group. Moreover, our results showed that altered serum levels of ß-hCG can have a substantial impact on the early detection of clinically relevant copy number variants. DISCUSSION/CONCLUSION: Traditional cFTS can potentially identify a substantial proportion of atypical chromosomal aberrations, and women with increased NT or low maternal serum ß-hCG levels are at increased risk of having pathogenic CMA results. Our results may help clinicians and women decide whether invasive testing or prenatal cell-free DNA screening testing is more appropriate for each situation.

Utilidad de los marcadores bioquímicos de preeclampsia / Usefulness of the biochemical markers of pre-eclampsia

La preeclampsia (PE) constituye una de las principales causas de mortalidad materna y perinatal en el mundo. En los países desarrollados, los estudios apuntan a un importante aumento de la incidencia de PE en la última década, en parte, por el aumento de la prevalencia, en la población general, de enfermedades que afectan a la función vascular, como la diabetes, la hipertensión crónica o la enfermedad renal. En el presente documento se lleva cabo una revisión actualizada de la PE. Se describen los criterios diagnósticos y la fisiopatología de la enfermedad. El objetivo principal del documento es revisar los nuevos marcadores bioquímicos que pueden ser de utilidad en la práctica clínica para la predicción y el diagnóstico de la PE, así como los distintos métodos mediante los cuales se puede llevar a cabo su determinación

Pre-eclampsia (PE) is one of the leading causes of maternal and perinatal mortality in the world. In developed countries, studies point to a significant increase in the incidence of PE in the last decade, partly due to the increase in the prevalence in the general population of diseases that affect vascular function, such as diabetes. chronic hypertension, or kidney disease. An updated review of PE is presented in this article. The diagnostic criteria and the pathophysiology of the disease are described. The main objective of the document is to review the new biochemical markers that may be useful in clinical practice for the prediction and diagnosis of PE, as well as the different methods by which yey can be determined

Pituitary-ovary axis and ovarian reserve in fertile women with multiple sclerosis: A pilot study.

Since a decline in the ovary function might impact the reproductive potential in women with multiple sclerosis (MS), we investigated the pituitary-ovary axis and ovarian reserve, including anti-Müllerian hormone (AMH) levels and ultrasound imaging of the ovaries, of 25 relapsing-remitting MS patients and 25 age-matched healthy controls. Mean levels of pituitary-gonadal hormones and age-adjusted parameters of ovarian reserve markers were not significantly different between both groups. Patients with higher disease activity (annualized relapse rate >0.5; n=9) had significantly lower AMH levels, total antral follicle count and ovarian volume, than those with lower disease activity. The finding of poorer ovarian reserve associated with higher disease activity should be taken into consideration since it may negatively impact the reproductive prognosis.

Recomendaciones para el uso clínico del microarray genómico en diagnóstico prenatal / Recommendations for the clinical use of genomic microarray in prenatal diagnosis

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Estado actual del cribado prenatal de cromosomopatías en España: resultados encuesta SEQC 2013 / Present situation of prenatal screening of chromosomopathies in Spain: SEQC survey results 2013

En los últimos 30 años se han desarrollado numerosas estrategias de cribado prenatal de aneuploidías mediante marcadores bioquímicos y/o ecográficos. En España no existió una política uniforme y global para el cribado prenatal hasta que, en 2005, la Sociedad Española de Ginecología y Obstetricia (SEGO) recomendó descartar la EM avanzada como única indicación para realizar prueba invasiva y propuso implantar el test combinado en todo el territorio español. Sin embargo, no hay evidencias de que exista una estrategia común. Además, los recientes avances en tecnología genómica han abierto las puertas al desarrollo de nuevas estrategias de cribado basadas en el uso del ADN fetal en sangre materna. A la espera de evidencias objetivas sobre la eficacia de estas nuevas estrategias no invasivas en población de bajo riesgo, sería muy deseable conocer la eficacia de los cribados actuales para comparar con las estrategias futuras y, sobre todo, para tener en cuenta algunas recomendaciones recientes en nuestro país. El presente trabajo describe la situación actual del cribado prenatal de aneuploidías en España, mediante el análisis de los datos recogidos en un sondeo en el que participaron 97 centros públicos y privados que realizan cribado de cromosomopatías en nuestras comunidades autónomas. Con este estudio, el grupo de trabajo de Diagnóstico Prenatal de la SEQC pretende animar a la coordinación y el diálogo de todos los implicados en los procesos de cribado prenatal de aneuploidías, con vistas a consensuar los protocolos existentes en las distintas autonomías (AU)

During the last 30 years, numerous strategies for prenatal screening of aneuploidies have been developed using sonographic and biochemical markers. In Spain, there were no uniform and global prenatal screening strategies in the different autonomous communities until 2005, when the Sociedad Española de Ginecología y Obstetricia (SEGO) recommended avoiding advanced maternal age as a unique indication for an invasive test and proposed the first trimester combined test implementation. However, there is no evidence yet that a uniform strategy exists. Moreover, the recent advances on genomics have open up the door to the development of new screening strategies based on using fetal DNA recovered from maternal blood. Waiting for objective evidences about the efficacy of these new non-invasive strategies in low-risk population, it would be desirable to know the efficacy of present screening programs to compare them with future strategies and, to pay attention to some recent recommendations in our country. The present work describes the present situation of prenatal screening of aneuploidies in Spain, by analysing data from a survey on 97 public and private centers envolved on chromosomopathies screening in our autonomic communities. With this study, the Prenatal Diagnosis workgroup of the SEQC aims to impulse the coordination and the dialog of all agents implicated into aneuploidies prenatal screening programs in order to achieve a consensued protocol along the different autonomies (AU)

Recomendaciones para la aplicación clínica de la detección de aneuploidías en ADN fetal libre en sangre materna / Recommendations for the clinical application of aneuploidy detection in cell-free fetal DNA in maternal blood

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Forms of Circulating Luteinizing Hormone Human Chorionic Gonadotropin Receptor for the Prediction of Early and Late Preeclampsia in the First Trimester of Pregnancy.

OBJECTIVE: To explore the value of circulating luteinizing human chorionic gonadotropin receptor (LHCGR) forms for the prediction of preeclampsia (PE) in the first trimester of pregnancy. METHODS: Case-control study, based on a cohort of 5,759 pregnancies, including 20 early PE, 20 late PE, and 300 controls. We recorded/measured maternal characteristics, mean arterial pressure (MAP), uterine artery (UtA) Doppler, placental growth factor (PlGF), soluble Fms-like tyrosine kinase-1 (sFtl-1), and LHCGR forms (hCG-LHCGR and soluble LHCGR), and their independent predictive values were analyzed by logistic regression. RESULTS: For early PE, the model included black ethnicity, chronic hypertension, previous PE, MAP, UtA Doppler, PlGF, sFlt-1, and LHCGR forms, achieving detection rates (DR) of 83% at 10% of false-positive rates (FPR) [AUC: 0.961 (95% CI: 0.921-1)]. For late PE, the model included body mass index, previous PE, UtA Doppler, PlGF, sFlt-1, and LHCGR forms, with DR of 75% at 10% of FPR [AUC: 0.923 (95% CI: 0.871-0.976)]. In both early and late PE, LHCGR forms improved DR by 6-15%. CONCLUSIONS: LHCGR forms improved the prediction for early and late PE. These results should be confirmed in larger prospective studies.

The utility of circulating LHCGR as a predictor of Down's syndrome in early pregnancy.

BACKGROUND: Previous studies showed that soluble LHCGR/hCG-sLHCGR concentrations in serum or plasma combined with PAPP-A and free ßhCG significantly increased the sensitivity of Down's syndrome screen at early pregnancy without altering the false positive rate. The goal of the present study was to further examine the role of sLHCGR forms as combinatorial markers and to investigate whether sLHCGR could serve as an independent biomarker for Down's syndrome in first trimester pregnancy screens. METHODS: The PAPP-A, free ßhCG, and hCG-sLHCGR concentrations together with nuchal translucency (NT) were measured in 40 Down's and 300 control pregnancies. The sLHCGR concentration was analysed in 40 Down's and 206 control pregnancies. RESULTS: The hCG-LHCGR in combination with PAPP-A and free ßhCG increased the detection rate (DR) by 35% without altering the false positive rate (FPR). The sLHCGR: hCG-sLHCGR ratio alone detected 80% of Down's pregnancies in first trimester screening, with a false positive rate of 0.5%. CONCLUSIONS: While measurement of sLHCGR forms in combination with PAPP-A and free ßhCG significantly increases the detection rate of Down's syndrome at first trimester, the ratio of sLHCGR: hCG-sLHCGR acts as an independent marker with a detection rate that is significantly higher than the existing biochemical markers individually for prenatal first trimester screening of Down's syndrome.

First-trimester Down syndrome screening in renal-transplanted pregnant women: a model for adjusting the false-positives rates.

OBJECTIVE: This study aimed to develop a model to adjust the increased ß-hCG levels observed in renal-transplanted women, leading to increased false-positive rates in Down syndrome screening. METHODS: Detailed data from 11 renal-transplanted and a nested-cohort of 70 pregnant women, matched by age, parity and gestational age were retrieved from our hospital records. Patient's age, multiples of the median (MoM) values for freeß-hCG, pregnancy-associated plasma protein-A, nuchal translucency, and creatinine concentration and clearance were noted. Freeß-hCG levels were adjusted according to the deviation of serum creatinine concentration by means of three different methods (median, proportionality and regression). Subsequently, Down syndrome risk was estimated with the three resulting adjusted fß-hCG values. RESULTS: After adjustment, the median ß-hCG MoM decreased from 2.15 MoM to 1.00 MoM (median method), 1.61 MoM (proportionality method) or 1.16 MoM (regression method). The non-adjusted 27% false-positive rate dropped to 18% (median method) and 10% (proportionality or regression methods) after re-estimation of the Down syndrome risk. In controls, the observed median for ß-hCG MoM was 1.12, and the false-positive rate was 5.7%. CONCLUSIONS: In first-trimester Down syndrome screening, fß-hCG adjustment by the regression method appears to be the best to match with controls.

Utilidad de la inhibina A en el cribado de síndrome de Down en el segundo trimestre / Inhibin A in second trimester screening of Down's syndrome

Objetivo. Comprobar la eficacia de la incorporación de la inhibina A en el cribado de segundo trimestre del síndrome de Down en términos de tasa de detección y porcentaje de cribados positivos. Métodos. Estudio retrospectivo de 3.380 embarazadas, que se sometieron al cribado de segundo trimestre, clasificadas en 2 grupos en función de la incorporación de la inhibina A (1.921 mujeres) o no (1.459 mujeres).Resultados. La tasa de detección con un punto de corte de 1:250 fue del 90% en el grupo de inhibina A y 84,6% sin inhibina A, pero con un porcentaje de cribados positivos significativamente menor en el primero (11 vs. 15,9%; p < 0,001). Este concepto también se refleja al comparar el likelihood ratio positivo entre ambos grupos (8,47 vs. 5,54; p <0,001). Conclusión. Es aconsejable la incorporación de la inhibina A en el cribado de segundo trimestre, ya que se observa un menor porcentaje de casos positivos, con la consiguiente reducción en el número de amniocentesis a realizar(AU)

Objective. To evaluate the efficacy of inhibin A in second trimester screening of Down's syndrome in terms of detection rate and percentage of positive results. Methods. A retrospective study of 3380 pregnant women who underwent second trimester screening, classified into 2 groups, one which included inhibin A (1921 pregnant women) and one that did not (1459 pregnant women). Results. The detection rate (cut-off: 1:250) was 90% in the group with inhibin A and 84.6% in the other group, but the percentage of positive results was significantly lower in the first group (11% vs. 15.9%, P<.001). The results were similar if we compared the positive likelihood ratio between groups (8.47 vs. 5.54, P<.001). Conclusion. Inhibin A is a useful marker in second trimester screening due to the low percentage of positive cases observed, thereby reducing the number of amniocentesis(AU)

Effect of a traditional Mediterranean diet on apolipoproteins B, A-I, and their ratio: a randomized, controlled trial.

OBJECTIVES: Apolipoprotein (Apo)B, ApoA-I, and their ratio could predict coronary heart disease (CHD) risk more accurately than conventional lipid measurements. Our aim was to assess the effect of a traditional Mediterranean diet (TMD) on apolipoproteins. METHODS: High-cardiovascular risk subjects (n=551, 308 women and 243 men), aged 55-80 years, were recruited into a large, multicenter, randomized, controlled, parallel-group, clinical trial (The PREDIMED Study) aimed at testing the efficacy of TMD on primary cardiovascular disease prevention. Participants assigned to a low-fat diet (control) (n=177), or TMDs (TMD+virgin olive oil (VOO), n=181 or TMD+nuts, n=193) received nutritional education and either free VOO (ad libitum) or nuts (dose: 30 g/day). A 3-month evaluation was performed. RESULTS: Both TMDs promoted beneficial changes on classical cardiovascular risk factors. ApoA-I increased, and ApoB and ApoB/ApoA-I ratio decreased after TMD+VOO, the changes promoting a lower cardiometabolic risk. Changes in TMD+VOO versus low-fat diet were -2.9 mg/dL (95% CI, -5.6 to -0.08), 3.3mg/dL (95% CI, 0.84 to 5.8), and -0.03 mg/dL (-0.05 to -0.01) for ApoB, ApoA-I, and ApoB/ApoA-I ratio, respectively. CONCLUSIONS: Individuals at high-cardiovascular risk who improved their diet toward a TMD pattern rich in virgin olive oil, reduced their Apo B and ApoB/ApoA-I ratio and improved ApoA-I concentrations.

Gestational age-specific cutoff levels of TDx-FLM II for the prediction of neonatal respiratory distress syndrome.

AIM: To construct a predictive model for respiratory distress syndrome (RDS) from gestational age (GA) at delivery and TDx-FLM II value. METHODS: Pregnant women who underwent an amniocentesis in which TDx-FLM II was determined were included in the study. A model for the occurrence of RDS was constructed by means of a logistic regression procedure from TDx-FLM II values and GA at delivery. RESULTS: The mean value of TDx-FLM II was 47.11 mg/g. The mean GA at delivery was 33.4 weeks. The incidence of RDS was 7.8% (18/231). The optimal cutoff of predicted risk for respiratory distress was found to be 8.8%, resulting in a sensitivity and specificity of 89 and 83%, respectively. CONCLUSIONS: The adjustment of the TDx-FLM II value for GA at delivery results in a significant improvement in the predictive capacity of the test for the occurrence of RDS. The use of GA-specific cutoff values may simplify clinical decisions.

Cribado de aneuploidía en gestación gemelar: resultados de la aplicación del test combinado / Trisomy 21 screening in twin pregnancies: results of the application of the combined test

Objetivo: Descripción de la efectividad del test combinado en gestaciones gemelares. Descripción del valor de los marcadores bioquímicos y de la medición de la translucencia nucal (TN) en gestaciones con fetos euploides y en gestaciones con algún feto afectado. Comparación de los marcadores en función de la corionicidad y del tipo de fecundación, espontánea o asistida.Material y métodos: Estudio retrospectivo de 161 gestaciones gemelares. La determinación bioquímica (fracción beta libre de la gonadotropina coriónica humana [fß-hCG] y proteína plasmática A asociada al embarazo [PAPP-A]) se realizó entre las 8 y las 12 semanas y la medición de la TN entre las 11 y las 14 semanas. Con la aplicación del test combinado se calculó el riesgo de trisomía 21 para cada feto. En gestaciones monocoriales se calculó un único riesgo con la TN mayor. Se recomendó un procedimiento invasivo cuando el riesgo era >= 1/250 en uno o ambos fetos. Resultados: El test combinado mostró una sensibilidad del 100% para la detección de trisomía 21 (3 gestaciones y 4 fetos) para una tasa de falsos positivos del 6,4% de las gestaciones y 3,5% de los fetos. Las mediana de la fß-hCG fue 1,72 MoM, la PAPP-A 2,01 MoM y la TN 1,05 MoM. En las gestaciones monocoriales la mediana de la fß-hCG y de la PAPP-A fue significativamente menor que en las gestaciones dicoriales y la PAPP-A fue significa-tivamente menor en las gestaciones procedentes de reproducción asistida. No se observaron diferencias en la medición de la TN en función de la corionicidad ni del tipo de fecundación. Conclusiones: El test combinado en la gestación gemelar muestra una sensibilidad y una especificidad elevadas. Se observan algunas diferencias en el valor de los marcadores bioquímicos en función de la corionicidad y del antecedente de reproducción asistida, pero estas diferencias deberían confirmarse con un número mayor de casos

Objective: To evaluate the effectiveness of the Combined Test for trisomy 21 screening in twin pregnancies. To assess the performance of biochemical markers and nuchal translucency (NT) measurement in pregnancies with euploid fetuses and in twin pregnancies with one or two affected fetuses. To compare the value of markers according to chorionicity and the mode of conception. Material and methods: Retrospective study including 161 twin pregnancies. Maternal serum fß-hCG and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 14 weeks. The individual risk of trisomy 21 was calculated in each fetus using the Combined Test. In monochorionic pregnancies, the single risk for the pregnancy was obtained with the largest NT. An invasive diagnostic procedure was offered when the risk was 1:250 or more in one or both of the fetuses. Results: All trisomy 21 pregnancies were identified (three pregnancies and four fetuses) by the combined testfor a false-positive rate of 6.4% of pregnancies and 3.5% of fetuses. The median fß-hCG level, expressed in MoM, was 1.72 and the median PAPP-A level was 2.01. The median NT was 1.05 MoM. Both fß-hCG and PAPP-A levels were significantly decreased in monochorionic pregnancies and PAPP-A was significantly decreased in pregnancies resulting from assisted reproduction. No significant differences were observed in NT measurement between monochorionic and dichorionic fetuses or between those conceived naturally or by assisted reproduction. Conclusions: The combined test shows high sensitivity and specificity in screening for trisomy 21 in twin pregnancies. The differences obtained in the biochemical markers according to chorionicity or the mode of conception require confirmation in further studies with a larger number or cases

Acute effects of high-fat meals enriched with walnuts or olive oil on postprandial endothelial function.

OBJECTIVES: We sought to investigate whether the addition of walnuts or olive oil to a fatty meal have differential effects on postprandial vasoactivity, lipoproteins, markers of oxidation and endothelial activation, and plasma asymmetric dimethylarginine (ADMA). BACKGROUND: Compared with a Mediterranean diet, a walnut diet has been shown to improve endothelial function in hypercholesterolemic patients. We hypothesized that walnuts would reverse postprandial endothelial dysfunction associated with consumption of a fatty meal. METHODS: We randomized in a crossover design 12 healthy subjects and 12 patients with hypercholesterolemia to 2 high-fat meal sequences to which 25 g olive oil or 40 g walnuts had been added. Both test meals contained 80 g fat and 35% saturated fatty acids, and consumption of each meal was separated by 1 week. Venipunctures and ultrasound measurements of brachial artery endothelial function were performed after fasting and 4 h after test meals. RESULTS: In both study groups, flow-mediated dilation (FMD) was worse after the olive oil meal than after the walnut meal (p = 0.006, time-period interaction). Fasting, but not postprandial, triglyceride concentrations correlated inversely with FMD (r = -0.324; p = 0.024). Flow-independent dilation and plasma ADMA concentrations were unchanged, and the concentration of oxidized low-density lipoproteins decreased (p = 0.051) after either meal. The plasma concentrations of soluble inflammatory cytokines and adhesion molecules decreased (p < 0.01) independently of meal type, except for E-selectin, which decreased more (p = 0.033) after the walnut meal. CONCLUSIONS: Adding walnuts to a high-fat meal acutely improves FMD independently of changes in oxidation, inflammation, or ADMA. Both walnuts and olive oil preserve the protective phenotype of endothelial cells.

Atherogenic lipoprotein subfraction profile in preeclamptic women with and without high triglycerides: different pathophysiologic subsets in preeclampsia.

Abnormal lipid metabolism has been proposed as a pathogenic factor of preeclampsia, although whether it is a constant feature in all preeclamptic patients is unclear. We assessed whether plasma triglyceride (TG) levels can distinguish a subgroup of preeclamptic women with alterations in lipoprotein profile from those with normal lipid metabolism and can be used to identify 2 distinct pathogenic groups in preeclampsia. This prospective study included 34 women with preeclampsia and 23 healthy pregnant women. Preeclamptic women were further subclassified into normal-TG (<250 mg/dL) and high-TG (>or=250 mg/dL) groups on the basis of the 90th percentile in our population. Low-density lipoproteins (LDLs) were ultracentrifuged and were separated into 4 subfractions, and lipid distribution in the subfractions was analyzed in all study groups. Vascular cell adhesion molecule-1 was also measured as a marker of endothelial dysfunction. Sixteen women with preeclampsia had high TGs (47% vs 13% in control subjects, P<.001). This subgroup showed a significant shift in lipid distribution, mainly, TGs, toward the small, dense LDL subfractions. However, preeclamptic patients in the normal-TG subgroup showed LDL subfraction lipid distribution similar to that of healthy pregnancies. Vascular cell adhesion molecule-1 levels were significantly elevated in preeclamptic patients in comparison with those in control subjects regardless of TG levels. The presence of a proatherogenic lipoprotein profile, previously described in preeclampsia, is characterized by increased small dense LDL and is exclusive to a subset of preeclamptic patients with high TG levels. These findings support the concept of heterogeneous pathogenic lines in preeclampsia and the use of subclassifications in pathophysiologic research on this condition.

First-trimester screening for trisomy 21 in twin pregnancy: does the addition of biochemistry make an improvement?

OBJECTIVE: To evaluate the effectiveness of the addition of first-trimester biochemistry to fetal nuchal translucency (NT) measurement in the Combined Test when screening for trisomy 21 in twin pregnancies. METHODS: Maternal serum free beta-hCG and PAPP-A were determined at 8 to 12 weeks and fetal NT was measured at 11 to 14 weeks. The individual risks were estimated for each of the fetuses using both NT screening alone and the Combined Test. An invasive diagnostic procedure was offered when the risk was 1:250 or over in either one of the fetuses. In the first period, only the results of NT screening were clinically applied. After previous analysis, the Combined Test was introduced into clinical practice. RESULTS: In the two-and-a-half-year study period, a complete follow-up was obtained in 100 twin pregnancies. Three fetuses (two pregnancies) with trisomy 21 were detected by both methods. The false-positive rate achieved by NT screening (14.3% of pregnancies and 8.6% of fetuses) was substantially reduced when first-trimester biochemistry was added in the Combined Test (5.1% of pregnancies and 3.6% of fetuses). CONCLUSION: The Combined Test appears to maintain the detection rate achieved by NT screening for trisomy 21 in twin pregnancies, but false-positive rates and invasive diagnostic procedures are reduced.

First-trimester screening for trisomy 21 combining biochemistry and ultrasound at individually optimal gestational ages. An interventional study.

OBJECTIVE: To assess the effectiveness of the Combined Test in the prenatal detection of trisomy 21 in the general pregnant population using a new timing for the screening approach. METHODS: First-trimester maternal serum biochemical markers (pregnancy-associated plasma protein-A and free-beta hCG) were determined in maternal serum at 7 to 12 weeks. Fetal nuchal translucency and gestational age were assessed at the 10- to 14-week ultrasound scan. A combined risk was estimated and delivered to the women the same day. When the risk was 1:250 or above, chorionic villus sampling was offered. RESULTS: Mean gestational age at biochemistry was 9.4 weeks, being 12.3 at ultrasound. In the 2780 studied pregnancies with a complete follow-up, observed detection rates were 88% (7/8) for trisomy 21 and 75% (3/4) for trisomy 18, with a 3.3% (92/2765) false-positive rate. CONCLUSION: The Combined Test, assessing biochemistry and ultrasound at individually optimal ages in the first trimester, showed an 88% detection rate for trisomy 21 with a remarkably reduced false-positive rate (3.3%).

High-density lipoproteins reduce the effect of endotoxin on cytokine production and systemic hemodynamics in cirrhotic rats with ascites.

BACKGROUND/AIMS: Hypersensitivity to endotoxin is a recognized feature in cirrhosis. High-density lipoproteins (HDL) have a high capacity to inactivate endotoxin. The aim was to determine if HDL reduces the effect of endotoxin on cytokine production and systemic hemodynamics in experimental cirrhosis. METHODS: The study was performed in control and rats with carbon-tetrachloride induced cirrhosis with ascites. Hemodynamic parameters were determined before and after several doses of endotoxin. The effects of 25 microg/kg of endotoxin on the serum concentration of TNFalpha and mean arterial pressure (MAP) were determined after treatment with HDL (80 mg/kg) or saline. RESULTS: Whereas endotoxin decreased MAP only at doses of 100 and 1000 microg/kg in control rats, in cirrhotic rats significant hypotension occurred at doses of 25, 50, 100 and 1000 microg/kg. Following the administration of endotoxin (25 microg/kg) the serum levels of TNFalpha were 140 times higher in cirrhotic than in control rats (89?835+/-21?090 vs. 625+/-137 pg/ml; P<0.001). Serum TNFalpha was 80% lower in cirrhotic rats pretreated with HDL (18?890+/-5012 pg/ml; P<0.001) than in those pretreated with saline. The administration of endotoxin (25 microg/kg) was associated with a significant lower decrease of MAP in cirrhotic rats pretreated with HDL than in those receiving saline (11.9+/-3.5 vs. 24.7+/-4.3%; P<0.05). CONCLUSIONS: HDL attenuates the increased effect of endotoxin on cytokine production and systemic hemodynamic in cirrhosis.

A walnut diet improves endothelial function in hypercholesterolemic subjects: a randomized crossover trial.

BACKGROUND: Epidemiological studies suggest that nut intake decreases coronary artery disease (CAD) risk. Nuts have a cholesterol-lowering effect that partly explains this benefit. Endothelial dysfunction is associated with CAD and its risk factors and is reversed by antioxidants and marine n-3 fatty acids. Walnuts are a rich source of both antioxidants and alpha-linolenic acid, a plant n-3 fatty acid. METHODS AND RESULTS: To test the hypothesis that walnut intake will reverse endothelial dysfunction, we randomized in a crossover design 21 hypercholesterolemic men and women to a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced approximately 32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. After each intervention, we obtained fasting blood and performed ultrasound measurements of brachial artery vasomotor function. Eighteen subjects completing the protocol had suitable ultrasound studies. Compared with the Mediterranean diet, the walnut diet improved endothelium-dependent vasodilation and reduced levels of vascular cell adhesion molecule-1 (P<0.05 for both). Endothelium-independent vasodilation and levels of intercellular adhesion molecule-1, C-reactive protein, homocysteine, and oxidation biomarkers were similar after each diet. The walnut diet significantly reduced total cholesterol (-4.4+/-7.4%) and LDL cholesterol (-6.4+/-10.0%) (P<0.05 for both). Cholesterol reductions correlated with increases of both dietary alpha-linolenic acid and LDL gamma-tocopherol content, and changes of endothelium-dependent vasodilation correlated with those of cholesterol-to-HDL ratios (P<0.05 for all). CONCLUSIONS: Substituting walnuts for monounsaturated fat in a Mediterranean diet improves endothelium-dependent vasodilation in hypercholesterolemic subjects. This finding might explain the cardioprotective effect of nut intake beyond cholesterol lowering.

Rapamycin attenuates atherosclerosis induced by dietary cholesterol in apolipoprotein-deficient mice through a p27 Kip1 -independent pathway.

Activation of immune cells and dysregulated growth and motility of vascular smooth muscle cells contribute to neointimal lesion development during the pathogenesis of vascular obstructive disease. Inhibition of these processes by the immunosuppressant rapamycin is associated with reduced neointimal thickening in the setting of balloon angioplasty and chronic graft vessel disease (CGVD). In this study, we show that rapamycin elicits a marked reduction of aortic atherosclerosis in apolipoprotein E (apoE)-null mice fed a high-fat diet despite sustained hypercholesterolemia. This inhibitory effect of rapamycin coincided with diminished aortic expression of the positive cell cycle regulatory proteins proliferating cell nuclear antigen and cyclin-dependent kinase 2. Moreover, rapamycin prevented the normal upregulation of the proatherogenic monocyte chemoattractant protein-1 (MCP-1, CCL2) seen in the aorta of fat-fed mice. Previous studies have implicated the growth suppressor p27(Kip1) in the antiproliferative and antimigratory activities of rapamycin in vitro. However, our studies with fat-fed mice doubly deficient for p27(Kip1) and apoE disclosed an antiatherogenic effect of rapamycin comparable with that found in apoE-null mice with an intact p27(Kip1) gene. Taken together, these findings extend the therapeutic application of rapamycin from the restenosis and CGVD models to the setting of diet-induced atherosclerosis. Our results suggest that rapamycin-dependent atheroprotection occurs through a p27(Kip1)-independent pathway that involves reduced expression of positive cell cycle regulators and MCP-1 within the arterial wall.