1. An individual patient data (IPD) meta-analysis of randomized controlled trials (RCTs) was conducted to determine whether the use of vaginal progesterone in asymptomatic women with a sonographic short cervix (<25 mm) in the midtrimester reduces the risk of preterm birth and improves neonatal morbidity and mortality. We also sought to determine whether clinical benefits were associated with the administration of vaginal progesterone in singleton and twin gestations. IPD meta-analyses, in which original research data for each participant in a study are sought directly from the investigators of each trial, are the gold standard for summarizing evidence across clinical studies. Five trials were included with a total of 775 women and 827 infants. Treatment with vaginal progesterone was associated with a significant 42% reduction in the rate of preterm birth <33 weeks of gestation, as well as significant reductions in the risk for preterm birth <35, <34, <30, and <28 weeks of gestation. Moreover, there was a significant 43% decrease in composite neonatal morbidity and mortality, a lower rate of neonatal intensive care unit admission and requirement for mechanical ventilation, as well as a significantly lower rate of neonates with birthweights <1500 g. There were no significant differences in adverse events between the vaginal progesterone and placebo groups. In patients with twin gestations, there was a nonsignificant trend toward reduction in the rate of preterm birth <33 weeks of gestation and a significant reduction in the frequency of composite neonatal morbidity/mortality. This IPD meta-analysis provides compelling evidence of the benefit of vaginal progesterone to prevent preterm birth and neonatal morbidity/mortality in women with a sonographic short cervix. Additional randomized controlled trials are needed to allow better assessment of the efficacy of vaginal progesterone in women with twin gestations and a short cervix. 2. Cerebral palsy (CP) is a syndrome diagnosed as the presence of non-progressive movement disorders of developmental origins. It is a chronic condition with no effective cure. CP is commonly associated with diffuse white matter damage. There is strong evidence that neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP, particularly in preterm neonates. This year, the Branch aimed to explore the effectiveness of using nanodevices to deliver therapeutic agents across the blood-brain barrier using an animal model of CP. Affected rabbits were treated intravenously with either a saline solution, a drug known as NAC (N-acetyl-cysteine) or a dendrimer coupled with NAC (D-NAC). Newborn rabbits with CP treated with D-NAC on the first day of life showed a dramatic improvement and, within 5 days, were able to walk and hop, while those untreated could not. Newborn rabbits treated with D-NAC also showed a higher neuron count and evidence of reduced inflammation compared to untreated animals. This work indicates that targeted attenuation of ongoing neuroinflammation may have significant implications for the treatment of maternal intrauterine infection and inflammation-induced brain injury, which leads to disorders including CP. The effectiveness of postnatal D-NAC treatment points to a new window of therapeutic opportunity for conditions such as motor and cognitive deficits originating in utero. The use of dendrimers to deliver therapeutic agents also may prove useful for other neuroinflammatory disorders. 3. High mobility group box-1 (HMGB1) protein is an alarmin (a normal cell constituent released into the extracellular environment upon cellular stress/damage) capable of activating inflammation and tissue repair. The receptor for advanced glycation end products (RAGE) can bind HMGB1. RAGE, in turn, can induce the production of pro-inflammatory cytokines;this may be modulated by the soluble truncated forms of RAGE, including soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE). We conducted a series of studies to determine whether: 1) clinical chorioamnionitis (CA) at term is associated with changes in amniotic fluid (AF) concentrations of HMGB1, sRAGE and esRAGE;and 2) the AF concentration of HMGB1 changes with labor or as a function of gestational age. AF samples were collected from the following groups: 1) mid-trimester (n=45);2) term with (n=48) and without labor (n=22) without intra-amniotic infection;and 3) term with CA (n=46). The results were: 1) the median AF HMGB1 concentration was higher in patients at term with clinical CA than in those without this condition;2) in contrast, patients with clinical CA had a lower median sRAGE concentration than those without CA;3) AF concentrations of esRAGE did not significantly change in patients with clinical CA at term;and 4) there was no significant difference in the median AF HMGB1 concentration between women at term in labor and those not in labor and between women in the mid-trimester and those at term not in labor. The findings suggest that an increase in the AF HMGB1 concentration and a decrease in sRAGE were observed in clinical CA at term and provides evidence that an alarmin, HMGB1, and one of its receptors, sRAGE, are engaged in the process of clinical CA at term. These changes are quite different from those observed in cases of intra-amniotic infection/inflammation in preterm gestations. 4. The human placenta is at the epicenter of the feto-maternal interface, and maternal cells of the decidua interact directly with fetal cells, typically trophoblasts, beginning at implantation and continuing throughout pregnancy. Decidual macrophages (dM) of the mother and placental macrophages (Hofbauer cells, HC) of the fetus are deployed at the feto-maternal interface. We conducted a series of studies to characterize the DNA methylome of maternal and fetal monocytes, dM, and HC and to determine the immunobiological importance of DNA methylation in pregnancy. Paired samples were obtained from normal pregnant women at term not in labor and their neonates. Maternal monocytes (MMo) and fetal monocytes (FMo) were isolated from the peripheral blood of mothers and fetal cord blood, respectively. dM and HC were obtained from the decidua of fetal membranes and placentas, respectively. The findings were: 1) significant differences in DNA methylation were found in each comparison (MMo versus FMo, 65 loci;dM versus HC, 266 loci;MMo versus dM, 199 loci;FMo versus HC, 1030 loci);2) many of the immune response-related genes were hypermethylated in fetal cells (FMo and HC) compared to maternal cells (MMo and dM);3) genes encoding markers of classical macrophage activation were hypermethylated, and genes encoding alternative macrophage activation were hypomethylated in dM and HC compared to MMo and FMo, respectively;4) mRNA expression of DNMT1, DNMT3A, and DNMT3B were significantly lower in dM than in HC;and 5) 5-azacytidine treatment increased expression of INCA1 in dM. These findings indicate that DNA methylation patterns change during monocyte-macrophage differentiation at the feto-maternal interface. They also suggest that DNA methylation is an important component of the biological machinery conferring an anti-inflammatory phenotype to macrophages at the feto-maternal interface.
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