Neutrophil gelatinase-associated lipocalin serum evaluation through normal pregnancy and in pregnancies complicated by preeclampsia.

Neutrophil gelatinase-associated lipocalin (NGAL) was evaluated prospectively through normal pregnancy and pregnancies complicated by preeclampsia syndrome. Sixty women enrolled in the study were evaluated for serum NGAL levels at 9-11 weeks gestation, at 24-26 weeks gestation and at delivery. Thirty women were affected by preeclampsia and 30 women with uncomplicated pregnancies formed the control group. NGAL serum concentrations in the preeclampsia group were higher compared to the control group, with significant differences in each trimester. In the first trimester, the median values were: 29.9 ng/mL [interquartile range (IQR) 24.1-50.1] versus 13.6 ng/mL (IQR 9.1-19.9; p < 0.001); in the second trimester: 59.6 ng/mL (IQR 25.3-82.6) versus 16.3 ng/mL (IQR 11.3-23.3; p < 0.001); and in the third trimester: 57.2 ng/mL (IQR 18.7-70.9) versus 15.8 ng/mL (IQR 9.1-22.5; p < 0.001). NGAL serum values were positively correlated with systolic and diastolic blood pressure and with proteinuria.

Second trimester neutrophil gelatinase-associated lipocalin as a potential prediagnostic marker of preeclampsia.

Neutrophil gelatinase-associated lipocalin (NGAL) concentrations, a product of neutrophils, were investigated in normal and preeclamptic pregnancies. Prospectively collected data and late second trimester (24-26 weeks) serum samples from 48 women who subsequently developed preeclampsia (PE) and 96 control women with uncomplicated pregnancies were compared. Serum NGAL values, as determined by quantitative sandwich enzyme immunoassay, were significantly increased in the preeclamptic compared to the control women: 76.9 ng/ml (interquartile range 39.7-96.5) versus 16.0 ng/ml (interquartile range 11.2-24.4) (p<0.001), and were positively correlated to blood pressure and proteinuria, showing a high sensitivity (75%) and specificity (94.5%). The results suggest that serum NGAL might be involved in the pathophysiology of PE and could be a marker for this syndrome.

Endoglin, PlGF and sFlt-1 as markers for predicting pre-eclampsia.

OBJECTIVE: To evaluate the ability of endoglin, placental growth factor (PlGF) and the soluble form of vascular endothelial growth factor receptor (sFlt-1) measurements in gestational weeks 24-28 were used to predict pre-eclampsia. DESIGN: Observational, prospective study. Setting. Department of Gynecological, Obstetrical Sciences and Reproductive Medicine, University of Messina. Sample. Fifty-two pre-eclamptic and 52 healthy pregnant women. METHODS: A maternal serum sample was frozen and stored at 1-h 50-g glucose challenge test between 24 and 28 weeks' gestation. A second maternal serum sample was collected at admission for the onset of the disease in the pre-eclamptic group and at admission for delivery in the control group. Levels of endoglin, sFlt-1 and the PlGF were measured in the stored serum. Pre-eclamptic subjects were also divided into women with early-onset (<37 weeks) and women with late-onset pre-eclampsia (> or =37 weeks). RESULTS: Levels of endoglin, sFlt-1, and sFlt-1:PlGF ratio were found to be higher in the pre-eclamptic group in both trimesters. No differences were found between early- and late-onset pre-eclamptic. The Receiver Operating Characteristics curve, applied to the second trimester marker values, showed the best diagnostic profile for sFlt-1:PlGF (area under the curve, AUC=0.92) followed by endoglin (AUC=0.88), sFlt-1 (AUC=0.87) and PlGF (AUC=0.83). This finding was confirmed by Bayesian analysis which highlighted a specificity, a sensitivity, a diagnostic accuracy, a positive predictive value and a negative predictive value of 88.5% for sFlt-1:PlGF using a cut-off of 38.47. CONCLUSIONS: Endoglin, PlGF and sFlt-1 might be used as markers for predicting pre-eclampsia, but sFlt-1:PlGF seems to be more accurate.

Incomplete penetrance of NRXN1 deletions in families with schizophrenia.

Neurexin 1 (NRXN1) is a presynaptic neuronal adhesion molecule that interacts with postsynaptic neuroligins in both glutamatergic and GABAergic synapses and is important in synaptic formation and function. NRXN1 deletions increase the risk of schizophrenia, so our aims were to explore this in our family sample, to distinguish de novo from inherited mutations, to examine transmission to affected and unaffected siblings and to estimate penetrance. We performed copy number analyses in NRXN1 using data from Illumina BeadArrays from 635 subjects with schizophrenia (276 in genotyped families), 487 of their unaffected parents and 309 unaffected siblings as well as 635 normal controls, all from the CBDB/NIMH Genetic Study of Schizophrenia. Deletions called by software were confirmed by quantitative PCR and comparative genome hybridization. There were deletions in 15 individuals in 11 families, including de novo exonic deletions in one case and one unaffected sibling. We observed no deletions in controls, 7 deletions in cases (1.10%), and an unexpectedly high deletion frequency in parents (n=5, 1.02%) and siblings (n=3, 0.97%). Three families showed inheritance from an unaffected parent, and in two families an unaffected parent did not transmit to the affected offspring. Thus we have added to the evidence that NRXN1 deletions are more frequent in patients with schizophrenia than in healthy individuals. However, the presence of de novo deletions in unaffected relatives and transmission from and to unaffected family members demonstrated that while the deletions may well have been necessary for some carriers to develop schizophrenia, they were not always sufficient.

Association of GSK-3ß genetic variation with GSK-3ß expression, prefrontal cortical thickness, prefrontal physiology, and schizophrenia.

OBJECTIVE Glycogen synthase kinase 3ß (GSK-3ß) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3ß gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3ß functional variation with 1) GSK-3ß mRNA expression from postmortem prefrontal cortex, 2) GSK-3ß and ß-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3ß (rs12630592) was associated with reduced GSK-3ß mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3ß protein expression and kinase activity, as well as with downstream effects on ß-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3ß variation is implicated in multiple phenotypes relevant to schizophrenia.