Fetal adrenal gland volume and cortisol/dehydroepiandrosterone sulfate ratio in inflammation-associated preterm birth

OBJECTIVE: Fetal adaptation to stress is regulated in part by the pituitary-adrenocortical system. The stress hormones dehydroepiandrosterone sulfate (DHEAS) and cortisol have opposing effects: cortisol suppresses while DHEAS enhances immune functions. We sought to estimate the impact of intraamniotic inflammation on fetal adrenal gland volume and cortisol-to-dehydroepiandrosterone sulfate ratio (fetal stress ratio) in pregnancies complicated by preterm birth. METHODS: Fifty-one consecutive singleton fetuses of mothers who had an indicated amniocentesis to rule out infection were analyzed. Intraamniotic inflammation was assessed by proteomic profiling of amniotic fluid for the biomarkers of the Mass Restricted score. The Mass Restricted score ranges from 0 (biomarkers absent) to 4 (all biomarkers present), with Mass Restricted scores of 3 or 4 indicating severe intraamniotic inflammation. Fetal adrenal gland volume was assessed by three-dimensional ultrasonography and corrected for estimated fetal weight. Interleukin-6 (IL-6), cortisol, and DHEAS were measured by immunoassay. RESULTS: Women with intraamniotic inflammation delivered earlier (27.8+/-3.4 weeks, n=16, compared with 32.3+/-3.0 weeks, n=35, P<.001), and their fetuses had higher cord blood IL-6 (P=.011) and higher corrected adrenal gland volumes (P=.027). Cord blood IL-6 levels were in direct relationship with corrected adrenal volume (r=0.372, P=.019), fetal cortisol (r=0.428, P=.010), and DHEAS (r=0.521, P<.001). However, fetuses exposed to intraamniotic inflammation had an overall lower fetal stress ratio (P=.034). These results maintained after adjusting for gestational age, uterine contractions, and steroid exposure. CONCLUSION: Fetuses exposed to intraamniotic inflammation have higher adrenal gland volumes and lower cortisol-to-DHEAS ratios, suggesting that the fetal adrenocortical axis plays a role in the intrauterine adaptation to inflammation.     

Fractional excretion of tumor necrosis factor-alpha in women with severe preeclampsia

OBJECTIVE: Proinflammatory cytokines of placental or systemic origin are thought to play a central role in the pathophysiology of preeclampsia. We sought to estimate the fractional excretion of tumor necrosis factor (TNF)-alpha in relationship to proteinuria in women with severe preeclampsia. METHODS: In a cross-sectional study, we evaluated the serum and urine levels of TNF-alpha in 45 women diagnosed with severe preeclampsia (mean+/-standard error of the mean, gestational age 29.1+/-0.5 weeks). Forty-five healthy pregnant women matched for parity, maternal age, and gestational age at recruitment (30.1+/-0.4 weeks) made up the control group. Urinary concentrations were normalized to creatinine. The fractional excretion of TNF-alpha was interpreted in relationship to that of total proteins and soluble fms-like tyrosine kinase-1 (sFlt-1). RESULTS: We found that the women with preeclampsia had significantly higher serum TNF-alpha concentrations compared with the women in the control group (mean+/-standard error of the mean, preeclampsia: 1.39+/-0.09 versus control: 0.93+/-0.07 pg/mL, P<.001). In contrast, urinary levels of TNF-alpha were significantly decreased in the women with preeclampsia compared with the healthy women (median [interquartile range], preeclampsia: 0.26 [0.10-0.91] versus control: 0.58 [0.21-1.29] pg/mg creatinine, P=.003), even though the hypertensive women had higher levels of proteinuria. In contrast to sFlt-1, urinary TNF-alpha did not correlate with the degree of proteinuria. Additionally, in preeclampsia, the fractional excretion of TNF-alpha was significantly lower (preeclampsia: 1.92% [0.46-4.20] versus control: 7.2% [2.44-12.07], P<.001). CONCLUSION: The fractional excretion of TNF-alpha is significantly reduced in women with severe preeclampsia despite proteinuria. The decreased clearance and altered renal excretion of this cytokine may contribute to the exaggerated inflammatory response observed in preeclampsia. LEVEL OF EVIDENCE: II.     

Single nucleotide polymorphisms in the human progesterone receptor gene and spontaneous preterm birth

Progesterone supplementation can prevent preterm birth in some high-risk women. Progesterone binds to progesterone receptor (PR) and modulates the expression of target genes. This study investigates the association between single nucleotide polymorphisms (SNPs) in the PR gene and spontaneous preterm birth. DNA was extracted from consecutive patients with preterm birth (n = 78) and term controls (n = 415), and genotyping was performed for 3 PR SNPs (+331[G>A], + 770[C>T], +660[G>T]) using Sequenom matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Data were analyzed by chi(2) test and logistic regression analysis. Multivariate analysis showed no association between maternal carriage of minor + 331T, +770T, and/or +660T alleles and preterm birth when controlled for maternal age, ethnicity, gravidity, parity, prior preterm birth, route of delivery, or neonatal outcome. Carriage of +770T and +660T (but not +331T) was associated with preterm birth in women with a body mass index <18.5 kg/m(2) (relative risk, 10.8; 95% confidence interval, 1.4-82.6; P = .02). Maternal carriage of minor alleles of +331(G>A), +770(C>T), and +660(G> T) SNPs in the PR gene is not associated with spontaneous preterm birth.     

Fetal heart rate monitoring patterns in women with amniotic fluid proteomic profiles indicative of inflammation

We hypothesized that abnormal fetal heart rate monitoring patterns (FHR-MPs) occur more often in pregnancies complicated by intra-amniotic inflammation. Therefore, our objective was to examine the relationships among FHR-MP abnormalities, intra-amniotic inflammation and/or infection, acute histological chorioamnionitis, and early-onset neonatal sepsis (EONS) in pregnancies complicated by preterm birth. Additionally, the ability of various FHR-MPs to predict EONS was investigated. FHR-MPs from 87 singleton premature neonates delivered within 48 hours from amniocentesis (gestational age, mean +/- SD: 28.9 +/- 3.3 weeks) were analyzed blindly using strict National Institute of Child Health and Human Development criteria. Strips were evaluated at three time points: at admission, at amniocentesis, and prior to delivery. Intra-amniotic inflammation was established based on a previously validated proteomic fingerprint (mass-restricted score). Diagnoses of histological chorioamnionitis and EONS were based on well-recognized pathological, clinical, and laboratory criteria. We determined that fetuses of women with severe intra-amniotic inflammation had a higher FHR baseline throughout the entire monitoring period and an increased frequency of a nonreactive FHR-MP at admission. Of all FHR-MPs, a nonreassuring test at admission had 32% sensitivity, 95% specificity, 73% positive predictive value, 77% negative predictive value, and 76% accuracy in predicting EONS. Although a nonreassuring FHR-MP at admission was significantly associated with EONS after correcting for gestational age (odds ratio, 5.6; 95% confidence interval, 1.2 to 26.2; P = 0.030), the majority of the neonates that developed EONS had an overall reassuring FHR-MP. Nonreassuring FHR-MPs at either amniocentesis or delivery had no association with EONS. We conclude that in cases complicated by preterm birth, a nonreassuring FHR-MP at the initial evaluation is a specific but not a sensitive predictor of EONS. An abnormal FHR-MP can thus raise the level of awareness that a fetus with EONS may be born, but it is not a useful clinical indicator of the need for antibiotic treatment of the neonate.     

Case of benralizumab‐induced exacerbations of chronic spontaneous urticaria

The role of IL‐5 in chronic spontaneous urticarial (CSU) is unclear. It may be that benralizumab is an important bidirectional modifier of CSU; that is, blocking IL‐5 may improve CSU in some patients, but it is possible that it may worsen CSU in others.     

National Scale Real-Time Surveillance of SARS-CoV-2 Variants Dynamics by Wastewater Monitoring in Israel

In this report, we describe a national-scale monitoring of the SARS-CoV-2 (SC-2) variant dynamics in Israel, using multiple-time sampling of 13 wastewater treatment plants. We used a combination of inclusive and selective quantitative PCR assays that specifically identify variants A19/A20 or B.1.1.7 and tested each sample for the presence and relative viral RNA load of each variant. We show that between December 2020 and March 2021, a complete shift in the SC-2 variant circulation was observed, where the B.1.1.7 replaced the A19 in all examined test points. We further show that the normalized viral load (NVL) values and the average new cases per week reached a peak in January 2021 and then decreased gradually in almost all test points, in parallel with the progression of the national vaccination campaign, during February–March 2021. This study demonstrates the importance of monitoring SC-2 variant by using a combination of inclusive and selective PCR tests on a national scale through wastewater sampling, which is far more amendable for high-throughput monitoring compared with sequencing. This approach may be useful for real-time dynamics surveillance of current and future variants, such as the Omicron (BA.1, BA.2) and other variants.     

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia

European Archives of Psychiatry and Clinical Neuroscience - Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the...     

Bioceramics Based on β-Calcium Pyrophosphate

Ceramic samples based on β-calcium pyrophosphate β-Ca₂P₂O₇ were prepared from powders of γ-calcium pyrophosphate γ-Ca₂P₂O₇ with preset molar ratios Ca/P = 1, 0.975 and 0.95 using firing at 900, 1000, and 1100 °C. Calcium lactate pentahydrate Ca(C₃H₅O₃)₂⋅5H₂O and monocalcium phosphate monohydrate Ca(H₂PO₄)₂⋅H₂O were treated in an aqua medium in mechanical activation conditions to prepare powder mixtures with preset molar ratios Ca/P containing calcium hydrophosphates with Ca/P = 1 (precursors of calcium pyrophosphate Ca₂P₂O₇). These powder mixtures containing calcium hydrophosphates with Ca/P = 1 and non-reacted starting salts were heat-treated at 600 °C after drying and disaggregation in acetone. Phase composition of all powder mixtures after heat treatment at 600 °C was presented by γ-calcium pyrophosphate γ-Ca₂P₂O₇ according to the XRD data. The addition of more excess of monocalcium phosphate monohydrate Ca(H₂PO₄)₂·H₂O (with appropriate molar ratio of Ca/P = 1) to the mixture of starting components resulted in lower dimensions of γ-calcium pyrophosphate (γ-Ca₂P₂O₇) individual particles. The grain size of ceramics increased both with the growth in firing temperature and with decreasing molar ratio Ca/P of powder mixtures. Calcium polyphosphate (t _melt = 984 °C), formed from monocalcium phosphate monohydrate Ca(H₂PO₄)₂⋅H₂O, acted similar to a liquid phase sintering additive. It was confirmed by tests in vitro that prepared ceramic materials with preset molar ratios Ca/P = 1, 0.975, and 0.95 and phase composition presented by β-calcium pyrophosphate β-Ca₂P₂O₇ were biocompatible and could maintain bone cells proliferation.