Circulating pregnancy hormone relaxin as a first trimester biomarker for preeclampsia.

OBJECTIVE: Preeclampsia, a multi-system hypertensive disorder, is associated with perturbations in the maternal cardiovascular system during early pregnancy. The corpus luteal hormone relaxin, a potent vasodilator, may contribute to physiological circulatory changes especially in early gestation when circulating levels are highest. This study investigated whether first trimester circulating relaxin may be a suitable biomarker for the early prediction of preeclampsia. METHODS: Relaxin was initially measured in first-trimester samples of women who developed late-onset preeclamptic (LO-PE; delivery ≥ 34 weeks; n = 33) and uncomplicated pregnancies (n = 25) in Pittsburgh, USA. Subsequently, to expand the group numbers, relaxin was measured in women who developed LO-PE (n = 95), early-onset preeclamptic (EO-PE; delivery < 34 weeks; n = 57), and uncomplicated pregnancies (n = 469) in Utrecht, the Netherlands. RESULTS: In the Pittsburgh subjects, low relaxin levels (lowest centile:

Obstructive sleep apnea may increase the risk of Alzheimer's disease.

OBJECTIVES: Amyloid-ß 1-40 (Aß 1-40) and amyloid-ß 1-42 (Aß 1-42) are the proteins known to be involved in the pathogenesis of Alzheimer's disease (AD)-the most common cause of dementia in the elderly. Hypoxia is suspected to be one of conditions associated with Aß plasma level increase. A common reason of hypoxia is obstructive sleep apnea (OSA), characterized by recurrent episodes of apnea. AIM: The aim of the study was to evaluate plasma Aß 1-40 and Aß 1-42 concentrations in patients with OSA. METHODS: Patients with suspected OSA (n = 112) underwent polygraphic examinations Patients with confirmed OSA (n = 81) showed apnea/hypopnea index greater than or equal to 5. Mild and moderate form of the disease was defined when AHI was 5-30 (n = 38, OSA+), severe-when AHI was >30 (n = 43, OSA++). Individuals with AHI<5 (n = 31) served as control group (OSA-). RESULTS: Aß 1-40 concentrations in OSA++ (191.1 pg/ml) group was significantly (p<0.05) higher compared with OSA- (76.9 pg/ml) and OSA+ (159.4 pg/ml) and correlated with selected parameters of hypoxemia severity. There were no differences in Aß 1-42 concentration between the groups. CONCLUSION: In patients with severe OSA Aß 1-40 plasma concentrations are significantly higher compared with OSA- and OSA+ and seem to be related to hypoxia severity, which may indicate increased risk of AD development in this group of patients.

Circulating Endothelial Microparticles and Aortic Stiffness in Patients with Type 2 Diabetes Mellitus.

Diabetes mellitus represents a metabolic disorder the incidence of which has been on the increase in recent years. The well-known long-term complications of this disease encompass a wide spectrum of renal, neurological and cardiovascular conditions. The aim of the study was to investigate the serum concentration of endothelial microparticles (EMPs) as well as selected noninvasive parameters of the ascending aorta stiffness calculated with echocardiography. In this study, 58 patients were enrolled-38 subjects diagnosed with type 2 diabetes mellitus (T2DM) and 20 healthy controls. The analyzed populations did not differ significantly with respect to age, renal function, systolic and diastolic blood pressure. The patients with diabetes and concomitant hypertension presented higher levels of EMPs in comparison with diabetic normotensive subjects. Among patients with diabetes and hypertension, aortic stiffness assessed with the elasticity index (Ep) was higher and the aortic compliance index (D) lower than in the diabetic normotensive group. No correlation between the amount of EMPs and lipid profile, C-reactive protein (CRP) level and glycemia, was observed in the studied group. There was, however, a statistically significant positive correlation between the creatinine level and amount of EMPs, while the negative relationship was documented for EMPs level and the estimated glomerular filtration rate (eGFR).

Spatial QRS-T angle in patients with newly diagnosed obstructive sleep apnea syndrome.

PURPOSE: The aim of the study was to assess the spatial QRS-T angle (QRS-TA) in a group of newly diagnosed and untreated adult patients with obstructive sleep apnea syndrome (OSAS) and to identify potential factors affecting this parameter. PATIENTS AND METHODS: The study group (PSG-confirmed OSAS) included 62 individuals, aged 51.7±10.3 years. The control group consisted of 25 individuals, aged 46.6±16.6 years with no sleep-disordered breathing. The diagnosis of OSAS and assessment of its severity was based on unattended all-night screening polysomnography. The spatial QRS-TA was reconstructed from 12-lead ECG using Kors' regression method. RESULTS: Significant differences of spatial QRS-TA values were found between patients with severe OSAS (36.9±18.9°) and the controls (20.3±13.4°; p<0.01) and between patients with mild or moderate OSAS (32.3±20.1°) and the controls (p=0.01). Statistically significant correlations were found between spatial QRS-TA and polysomnographic indices (i.e. AHI, AI, RDT and RDTI). CONLUSIONS: Spatial QRS-TA values are significantly higher in patients with OSAS than in controls, thus indicating increased heterogeneity of myocardial action potential. Further long-term prospective studies evaluating the prognostic value of spatial QRS-TA in OSAS patients are needed.

Reliability of the Epworth Sleepiness Scale and the Berlin Questionnaire for screening obstructive sleep apnea syndrome in the context of the examination of candidates for drivers.

BACKGROUND: The aim of the study has been to assess the usefulness of the Epworth Sleepiness Scale (ESS) and the Berlin Questionnaire (BQ) for obstructive sleep apnea syndrome (OSAS) screening. The capacity of both tests to discriminate between healthy individuals or with mild OSAS (apnea-hypopnea index (AHI) < 15/h) vs. patients with moderate or severe OSAS (AHI ≥ 15/h) was evaluated. MATERIAL AND METHODS: The study encompassed 223 patients with a suspicion of the OSAS. The ESS and BQ were completed by patients unassisted. Screening polysomnography was performed using the Porti SleepDoc. The OSAS was diagnosed when AHI ≥ 15/h or AHI ≥ 5/h with simultaneous occurrence of clinical symptoms. RESULTS: The ESS score was found to be significantly higher in the study group compared to the control group (8.9±5.9 vs. 11.6±5.2 pt, p < 0.0001). Otherwise, there were no significant inter-group differences in the percentage of high-risk individuals according to the BQ (83.7% vs. 92.3%, p > 0.05). Sensitivity of the ESS and BQ was 53.2% and 93.1%, respectively while specificity was 58.8% and 16.2%, respectively. Poor correlation between the ESS score and AHI and apnea index were noticed (r = 0.22, p = 0.001 and r = 0.24, p < 0.001, respectively). CONCLUSIONS: Considering its low sensitivity, the ESS should not be used as a screening test for the OSAS diagnosis amongst candidates for drivers. The BQ is characterised by high sensitivity for the OSAS diagnosis with AHI ≥ 15/h, however, due to low specificity, the questionnaire may increase the number of healthy individuals referred for needless diagnostic procedures. Med Pr 2016;67(6):721-728.

Evaluation of Fibrinolytic Inhibitors: Alpha-2-Antiplasmin and Plasminogen Activator Inhibitor 1 in Patients with Obstructive Sleep Apnoea.

Obstructive sleep apnoea (OSA) induces thrombophilia and reduces fibrinolysis. Alpha-2-antiplasmin (a-2-AP) and plasminogen activator inhibitor 1 (PAI-1) are major inhibitors of the fibrinolytic system. Increased concentrations of these factors are associated with a higher risk of cardiovascular diseases. The aim of this study was to assess plasma a-2-AP and PAI-1 in patients with OSA and evaluate correlations with the polysomnographic record and selected risk factors of cardiovascular diseases. The study group comprised 45 patients with OSA, and the control group consisted of 19 patients who did not meet the diagnostic criteria of OSA. Plasma a-2-AP and PAI-1 concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). In the study group, the median value of plasma a-2-AP was higher than that of the control group (157.34 vs. 11.89 pg/ml, respectively, P<0.0001). A-2-AP concentration increased proportionally to the severity of OSA. The concentration of a-2-AP was positively correlated with the apnoea-hypopnoea index (AHI), apnoea index (AI), respiratory disturbances time (RDT), and desaturaion index (DI), and negatively correlated with mean and minimal oxygen saturation (SpO2 mean, SpO2 min, respectively). The median value of PAI-1 was higher in the study group than the control group (12.55 vs. 5.40 ng/ml, respectively, P = 0.006) and increased along with OSA severity. PAI-1 concentration was positively correlated with AHI, AI, RDT, DI, and body mass index (BMI) and negatively correlated with SpO2 mean and SpO2 min. Higher plasma concentrations of a-2-AP and PAI-1 in patients with OSA indicated that these patients had increased prothrombotic activity. OSA increases the risk of cardiovascular complications as it enhances prothrombotic activity.

First-Trimester Serum Acylcarnitine Levels to Predict Preeclampsia: A Metabolomics Approach.

OBJECTIVE: To expand the search for preeclampsia (PE) metabolomics biomarkers through the analysis of acylcarnitines in first-trimester maternal serum. METHODS: This was a nested case-control study using serum from pregnant women, drawn between 8 and 14 weeks of gestational age. Metabolites were measured using an UPLC-MS/MS based method. Concentrations were compared between controls (n = 500) and early-onset- (EO-) PE (n = 68) or late-onset- (LO-) PE (n = 99) women. Metabolites with a false discovery rate <10% for both EO-PE and LO-PE were selected and added to prediction models based on maternal characteristics (MC), mean arterial pressure (MAP), and previously established biomarkers (PAPPA, PLGF, and taurine). RESULTS: Twelve metabolites were significantly different between EO-PE women and controls, with effect levels between -18% and 29%. For LO-PE, 11 metabolites were significantly different with effect sizes between -8% and 24%. Nine metabolites were significantly different for both comparisons. The best prediction model for EO-PE consisted of MC, MAP, PAPPA, PLGF, taurine, and stearoylcarnitine (AUC = 0.784). The best prediction model for LO-PE consisted of MC, MAP, PAPPA, PLGF, and stearoylcarnitine (AUC = 0.700). CONCLUSION: This study identified stearoylcarnitine as a novel metabolomics biomarker for EO-PE and LO-PE. Nevertheless, metabolomics-based assays for predicting PE are not yet suitable for clinical implementation.

Comparison of different blood collection, sample matrix, and immunoassay methods in a prenatal screening setting.

We compared how measurements of pregnancy-associated plasma protein A (PAPP-A) and the free beta subunit of human chorionic gonadotropin (fß-hCG) in maternal blood are influenced by different methods for blood collection, sample matrix, and immunoassay platform. Serum and dried blood spots (DBS) were obtained by venipuncture and by finger prick of 19 pregnant women. PAPP-A and fß-hCG from serum and from DBS were measured by conventional indirect immunoassay on an AutoDELFIA platform and by antibody microarray. We compared methods based on the recoveries for both markers as well as marker levels correlations across samples. All method comparisons showed high correlations for both marker concentrations. Recovery levels of PAPP-A from DBS were 30% lower, while those of fß-hCG from DBS were 50% higher compared to conventional venipuncture serum. The recoveries were not affected by blood collection or immunoassay method. The high correlation coefficients for both markers indicate that DBS from finger prick can be used reliably in a prenatal screening setting, as a less costly and minimally invasive alternative for venipuncture serum, with great logistical advantages. Additionally, the use of antibody arrays will allow for extending the number of first trimester screening markers on maternal and fetal health.

Metabolomics profiling for identification of novel potential markers in early prediction of preeclampsia.

OBJECTIVE: The first aim was to investigate specific signature patterns of metabolites that are significantly altered in first-trimester serum of women who subsequently developed preeclampsia (PE) compared to healthy pregnancies. The second aim of this study was to examine the predictive performance of the selected metabolites for both early onset [EO-PE] and late onset PE [LO-PE]. METHODS: This was a case-control study of maternal serum samples collected between 8+0 and 13+6 weeks of gestation from 167 women who subsequently developed EO-PE n = 68; LO-PE n = 99 and 500 controls with uncomplicated pregnancies. Metabolomics profiling analysis was performed using two methods. One has been optimized to target eicosanoids/oxylipins, which are known inflammation markers and the other targets compounds containing a primary or secondary biogenic amine group. Logistic regression analyses were performed to predict the development of PE using metabolites alone and in combination with first trimester mean arterial pressure (MAP) measurements. RESULTS: Two metabolites were significantly different between EO-PE and controls (taurine and asparagine) and one in case of LO-PE (glycylglycine). Taurine appeared the most discriminative biomarker and in combination with MAP predicted EO-PE with a detection rate (DR) of 55%, at a false-positive rate (FPR) of 10%. CONCLUSION: Our findings suggest a potential role of taurine in both PE pathophysiology and first trimester screening for EO-PE.

Maternal characteristics, mean arterial pressure and serum markers in early prediction of preeclampsia.

OBJECTIVES: In a previous study, we have described the predictive value of first-trimester Pregnancy-Associated Plasma Protein-A (PAPP-A), free ß-subunit of human Chorionic Gonadotropin (fß-hCG), Placental Growth Factor (PlGF) and A Disintegrin And Metalloprotease 12 (ADAM12) for early onset preeclampsia (EO-PE; delivery <34 weeks). The objective of the current study was to obtain the predictive value of these serum makers combined with maternal characteristics and first-trimester maternal mean arterial blood pressure (MAP) in a large series of patients, for both EO-PE and late onset PE (LO-PE; delivery ≥ 34 weeks). METHODS: This was a nested case-control study, using stored first-trimester maternal serum from women who developed EO-PE (n = 68) or LO-PE (n = 99), and 500 uncomplicated singleton pregnancies. Maternal characteristics, MAP, and pregnancy outcome were collected for each individual woman and used to calculate prior risks for PE in a multiple logistic regression model. Models containing prior PE risks, serum markers, and MAP were developed for the prediction of EO-PE and LO-PE. The model-predicted detection rates (DR) for fixed 10% false-positive rates were calculated for EO-PE and LO-PE with or without the presence of a small-for-gestational age infant (SGA, birth weight <10(th) centile). RESULTS: The best prediction model included maternal characteristics, MAP, PAPP-A, ADAM12, and PlGF, with DR of 72% for EO-PE and 49% for LO-PE. Prediction for PE with concomitant SGA was better than for PE alone (92% for EO-PE and 57% for LO-PE). CONCLUSION: First-trimester MAP, PAPP-A, ADAM12, and PlGF combined with maternal characteristics and MAP are promising markers in the risk assessment of PE, especially for EO-PE complicated by SGA.

Integrative data mining to identify novel candidate serum biomarkers for pre-eclampsia screening.

OBJECTIVE: Pre-eclampsia (PE) is a serious complication that affects approximately 2% of pregnant women worldwide. At present, there is no sufficiently reliable test for early detection of PE in a screening setting that would allow timely intervention. To help future experimental identification of serum biomarkers for early onset PE, we applied a data mining approach to create a set of candidate biomarkers. METHODS: We started from the disease etiology, which involves impaired trophoblast invasion into the spiral arteries. On the basis of this, we used a three-stage filtering strategy consisting of selection of tissue-specific genes, textmining for further gene prioritization, and identifying blood-detectable markers. RESULTS: This approach resulted in 38 candidate biomarkers. These include the best three first-trimester serum biomarkers for PE found to date LGALS13 (placental protein 13, PP13), PAPPA (pregnancy-associated plasma protein-A, PAPP-A), and PGF (placental growth factor, PlGF), as well as five proteins previously identified as biomarker after the first-trimester or disease onset. This substantiates the effectiveness of our approach and provides an important indication that the list will contain several new biomarkers for PE. CONCLUSIONS: We anticipate this list can serve in prioritization of future experimental studies on serum biomarkers for early onset PE.

Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for first-trimester prediction of preeclampsia: a systematic review.

UNLABELLED: Preeclampsia (PE) affects 1% to 2% of pregnant women and is a leading cause of maternal and perinatal morbidity and mortality worldwide. The clinical syndrome of PE arises in the second half of pregnancy. However, many underlying factors including defective placentation may already be apparent in the first and early second trimester in many patients. In clinical practice, there is currently no reliable screening method in the first trimester of pregnancy with sufficient accuracy to identify women at high risk to develop PE. Early identification of high-risk pregnancy may facilitate the development of new strategies for antenatal surveillance or prevention and thus improve maternal and perinatal outcome. The aim of this systematic review was to study the literature on the predictive potential of first-trimester serum markers and of uterine artery Doppler velocity waveform assessment (Ut-A Doppler). Literature on the 7 most studied serum markers (ADAM12, fß-hCG, Inhibin A, Activin A, PP13, PlGF, and PAPP-A) and Ut-A Doppler was primarily selected. In the selected literature, a combination of these markers was analyzed, and where relevant, the value of maternal characteristics was added. Measurements of serum markers and Ut-A Doppler were performed between week 8 + 0 and 14 + 0 GA. Low levels of PP13, PlGF, and PAPP-A and elevated level of Inhibin A have been found to be significantly associated with the development of PE later in pregnancy. The detection rates of single markers, fixed at 10% false-positive rate, in the prediction of early-onset PE were relatively low, and ranged from 22% to 83%. Detection rates for combinations of multiple markers varied between 38% and 100%. Therefore, a combination of multiple markers yields high detection rates and is promising to identify patients at high risk of developing PE. However, large scale prospective studies are required to evaluate the power of this integrated approach in clinical practice. TARGET AUDIENCE: Obstetricians and Gynecologists, Family physicians Learning Objectives: After completion of this article, the reader should be better able to appraise the recent literature on the development of preeclampsia in the first-trimester, evaluate the predictive value of first-trimester markers and use first-trimester markers, either individually or in combination, to assess the risk of preeclampsia.

[Serum creatinine level and eGFR as the indices of renal function in present-day clinical practice]. / Kreatyninemia oraz eGFR jako wykladniki funkcji nerek we wspólczesnej praktyce klinicznej.

The chronic kidney disease (CKD) is a polysymptomatic syndrome resulting from the reduction of active nephrons. It is estimated that the disease affects from 4.7-20% of adults. According to the actual knowledge, glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 is a significant risk factor for the cardiovascular diseases. The aim of our study was to assess the frequency of using the serum creatinine level and the estimated GFR (eGFR) as the indices of renal function in clinical practice. The study was performed amongst physicians working in non-academic departments of internal disease in the region of lubelskie voivodeships in 2008. An anonymous questionnaire of own composition consisting of 18 open and closed questions was used. The questions concerned the use of eGFR and serum creatinine level in everyday practice. 162 physicians were asked to fill the questionnaire, the percent of positive answers was 27.78% which is 45 questionnaires. The best parameter in evaluation of renal function, according to the asked physicians, was serum creatinine level (49% of all answers), eGFR (47%) and serum urea level or microalbuminuria (4%). Despite the actual recommendations, the serum creatinine level still remains the most popular routine parameter used to evaluate renal function. It seems that the knowledge concerning the diagnosing of CKD and the prophylaxis of its progression among physicians is insufficient. It concerns mainly physicians with no special training, working rather in profiled than in general medicine departments. Therefore, current educational programs concerning preventing and early diagnosis of CKD should be destinated mainly to these groups of physicians.

Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.

The mouse limb deformity (ld) mutations cause limb malformations by disrupting epithelial-mesenchymal signaling between the polarizing region and the apical ectodermal ridge. Formin was proposed as the relevant gene because three of the five ld alleles disrupt its C-terminal domain. In contrast, our studies establish that the two other ld alleles directly disrupt the neighboring Gremlin gene, corroborating the requirement of this BMP antagonist for limb morphogenesis. Further doubts concerning an involvement of Formin in the ld limb phenotype are cast, as a targeted mutation removing the C-terminal Formin domain by frame shift does not affect embryogenesis. In contrast, the deletion of the corresponding genomic region reproduces the ld limb phenotype and is allelic to mutations in Gremlin. We resolve these conflicting results by identifying a cis-regulatory region within the deletion that is required for Gremlin activation in the limb bud mesenchyme. This distant cis-regulatory region within Formin is also altered by three of the ld mutations. Therefore, the ld limb bud patterning defects are not caused by disruption of Formin, but by alteration of a global control region (GCR) required for Gremlin transcription. Our studies reveal the large genomic landscape harboring this GCR, which is required for tissue-specific coexpression of two structurally and functionally unrelated genes.