Inflammatory and haematological markers in the maternal, umbilical cord and infant circulation in histological chorioamnionitis

BACKGROUND: The relationship between histological chorioamnionitis and haematological and biochemical markers in mothers and infants at delivery, and in infants postnatally, is incompletely characterised. These markers are widely used in the diagnosis of maternal and neonatal infection. Our objective was to investigate the effects of histological chorioamnionitis (HCA) on haematological and biochemical inflammatory markers in mothers and infants at delivery, and in infants post-delivery. METHODS: Two hundred and forty seven mothers, delivering 325 infants, were recruited at the only tertiary perinatal centre in Western Australia. Placentae were assessed for evidence of HCA using a semi-quantitative scoring system. Maternal high sensitivity C-reactive protein (hsCRP), procalcitonin, and umbilical cord hsCRP, procalcitonin, white cell count and absolute neutrophil count were measured at delivery. In infants where sepsis was clinically suspected, postnatal CRP, white cell count and absolute neutrophil count were measured up to 48 hours of age. The effect of HCA on maternal, cord and neonatal markers was evaluated by multivariable regression analysis. RESULTS: The median gestational age was 34 weeks and HCA was present in 26 of 247 (10.5%) placentae. Mothers whose pregnancies were complicated by HCA had higher hsCRP (median 26 (range 2-107) versus 5.6 (0-108) mg/L; P<0.001). Histological chorioamnionitis was associated with higher umbilical cord hsCRP (75(th) percentile 2.91 mg/L (range 0-63.9) versus 75(th) percentile 0 mg/L (0-45.6); P<0.001) and procalcitonin (median 0.293 (range 0.05-27.37) versus median 0.064 (range 0.01-5.24) ug/L; P<0.001), with a sustained increase in neonatal absolute neutrophil count (median 4.5 (0.1-26.4)x10(9)/L versus 3.0 (0.1-17.8)x10(9)/L), and CRP up to 48 hours post-partum (median 10 versus 6.5 mg/L) (P<0.05 for each). CONCLUSION: Histological chorioamnionitis is associated with modest systemic inflammation in maternal and cord blood. These systemic changes may increase postnatally, potentially undermining their utility in the diagnosis of early-onset neonatal infection

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Dilute concentrations of maritime fuel can modify sediment reworking activity of high-latitude marine invertebrates

Multiple expressions of climate change, in particular warming-induced reductions in the type, extent and thickness of sea ice, are opening access and providing new viable development opportunities in high-latitude regions. Coastal margins are facing these challenges, but the vulnerability of species and ecosystems to the effects of fuel contamination associated with increased maritime traffic is largely unknown. Here, we show that low concentrations of the water-accommodated fraction of marine fuel oil, representative of a dilute fuel oil spill, can alter functionally important aspects of the behaviour of sediment-dwelling invertebrates. We find that the response to contamination is species specific, but that the range in response among individuals is modified by increasing fuel concentrations. Our study provides evidence that species responses to novel and/or unprecedented levels of anthropogenic activity associated with the opening up of high-latitude regions can have substantive ecological effects, even when human impacts are at, or below, commonly accepted safe thresholds. These secondary responses are often overlooked in broad-scale environmental assessments and marine planning yet, critically, they may act as an early warning signal for impending and more pronounced ecological transitions

Description of cases with histologic chorioamnionitis (HCA).

<p>Maternal and fetal inflammatory response were staged and graded according to criteria published by Redline <i>et al</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0051836#pone.0051836-Redline1" target="_blank">[18]</a>: *Maternal inflammatory response stage 0 = absent, 1 =  early, 2 =  intermediate, 3 =  advanced chorioamnionitis, grade 1 =  mild-moderate, 2 =  severe. #Fetal inflammatory response stage 0 =  absent, 1 =  early, 2 =  intermediate, 3 =  advanced funisitis, grade 1 =  mild-moderate, 2 =  severe. HCA was present if maternal response was grade/stage >1 and/or fetal response was grade/stage >0.</p><p>GA = gestational age, Single (S) = single gestation pregnancy, Multiple (M) = multiple gestation pregnancy, Bact. Cult. = bacterial culture result, <i>U. u</i> = <i>Ureaplasma</i> urealyticum, neg = negative, MCB = mixed coliform bacteria, <i>M. H</i> = <i>Mycoplasma</i> hominis, MBF = mixed bacterial flora, <i>C. A</i> = <i>Candida</i> albicans, MGF = mixed genital flora, <i>S. a</i> = <i>Staphylococcus</i> aureus, NA = not available.</p

C-reactive protein (CRP) concentrations in newborns with and without histologic chorioamnionitis (HCA) in the first hour (Day 0), 1–24 hours (Day 1) and 24–48 hours (Day 2) following delivery.

<p>C-reactive protein (CRP) concentrations in newborns with and without histologic chorioamnionitis (HCA) in the first hour (Day 0), 1–24 hours (Day 1) and 24–48 hours (Day 2) following delivery.</p

Demographic and clinical characteristics of maternal cases with and without histologic chorioamnionitis.

<p>Frequencies expressed as n(%) unless specified.</p>*<p>Median (Interquartile Range) [Range].</p>†<p>PROM = Premature rupture of membranes.</p><p>#PROM cases only ## Labour cases only.</p

Demographic and clinical characteristics of neonates with and without histologic chorioamnionitis.

<p>Frequencies expressed as n(%) unless specified *Median (Interquartile Range) [Range].</p>‡<p>SGA = Small for gestational age (<10^th percentile).</p

Transcription factor 3 is dysregulated in megakaryocytes in myelofibrosis

AbstractTranscription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical “MF-like” morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets