Perturbation of the ovine placental transcriptome occurs at sub-therapeutic exposures to antenatal steroid therapy.

Introduction: Antenatal steroid (ANS) therapy accelerates preterm lung maturation. Clinical and experimental data show current regimens disrupt placental function and transport and impact fetal growth. We have previously shown that higher materno-fetal steroid exposures increase fetal glucocorticoid clearance.

Transdermal delivery of antenatal steroids to promote fetal lung maturation: Proof of principle data from sheep and non-human primate models.

Background: Antenatal steroids (ANS) are routinely administered to women at risk of preterm birth to accelerate fetal lung maturation. Despite extensive clinical use, dosing and route of ANS administration remain unoptimized beyond intramuscular (IM) injection. We aimed to undertake a proof-of-principle assessment of transdermal ANS administration for accelerated fetal lung maturation.

Budesonide and hydrocortisone have differential effects on lung and brain in ventilated preterm lambs.

Background: Both the addition of budesonide to surfactant and prophylactic hydrocortisone show promise for decreasing lung inflammation without increasing neurodevelopmental changes in preterm infants. Determining if combining these postnatal steroid therapies with antenatal steroids is safe is essential.

Methods: Utilizing preterm sheep (n = 7-8/group) combining antenatal betamethasone (0.

Interleukin-1 Receptor Antagonists Partially Inhibited Histological Injury but Not Tissue Inflammation in a Sheep Model of Pregnancy.

Intrauterine inflammation is a significant cause of early preterm birth and fetal injury. There is a lack of effective interventions for intrauterine inflammation. This study aimed to determine whether direct fetal treatment with IL-1 receptor antagonists (IL-1RA), specifically anakinra (competitive IL-1RA) or rytvela (allosteric IL-1RA), could reduce intrauterine inflammation caused by intraamniotic injection of E.

Single-nucleotide polymorphisms in dizygotic twin ovine fetuses are associated with discordant responses to antenatal steroid therapy.

Background: Antenatal steroid (ANS) therapy is given to women at risk of preterm delivery to accelerate fetal lung maturation. However, the benefit of ANS therapy is variable and how maternal and fetal factors contribute to this observed variability is unknown. We aimed to test the degree of concordance in preterm lung function, and correlate this with genomic, transcriptomic, and pharmacokinetic variables in preterm dizygotic twin ovine fetuses.

Antenatal steroids elicited neurodegenerative-associated transcriptional changes in the hippocampus of preterm fetal sheep independent of lung maturation.

Background: Antenatal steroid therapy for fetal lung maturation is routinely administered to women at risk of preterm delivery. There is strong evidence to demonstrate benefit from antenatal steroids in terms of survival and respiratory disease, notably in infants delivered at or below 32 weeks' gestation. However, dosing remains unoptimized and lung benefits are highly variable.

Postnatal budesonide improved lung function in preterm lambs exposed to antenatal steroids and chorioamnionitis.

Background: A combination of budesonide and surfactant decreases the rates of BPD in infants and lung injury in preterm sheep. Whether this combination will show benefit in the setting of chorioamnionitis and antenatal steroids is not known.

Methods: Ewes at 123 ± 1 day gestational age received intra-amniotic (IA) injections of 10 mg LPS before being randomized to receive either 0.

Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy.

Objective: Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses.

Respiratory benefit in preterm lambs is progressively lost when the concentration of fetal plasma betamethasone is titrated below two nanograms per milliliter.

Antenatal steroid therapy is the standard of care for women at imminent risk of preterm delivery. Current dosing regimens use suprapharmacological doses to achieve extended fetal steroid exposures. We aimed to determine the lowest fetal plasma betamethasone concentration sufficient to achieve functional preterm lung maturation.

Artificial placenta support of extremely preterm ovine fetuses at the border of viability for up to 336 hours with maintenance of systemic circulation but reduced somatic and organ growth.

Artificial placenta therapy (APT) is an experimental life support system to improve outcomes for extremely preterm infants (EPI) less than 1,000 g by obviating the need for pulmonary gas exchange. There are presently no long-term survival data for EPI supported with APT. To address this, we aimed to maintain 95d-GA (GA; term-150d) sheep fetuses for up to 2 weeks using our APT system.

High Expression of Adrenal Cortisol Synthases Is Acquired After Intrauterine Inflammation in Periviable Sheep Fetuses.

Context: Intrauterine inflammation, a representative stressor for the fetus, has been shown to alter the hypothalamus-pituitary-adrenal (HPA) axis reactivity in preterm fetuses and increase postnatal cortisol production. However, the mechanism of this alteration has not yet been elucidated.

Objective: We aimed to clarify the effects of endotoxin-induced intrauterine inflammation on the HPA axis of periviable sheep fetuses.

A Reduction in Antenatal Steroid Dose Was Associated with Reduced Cardiac Dysfunction in a Sheep Model of Pregnancy.

Despite widespread use, dosing regimens for antenatal corticosteroid (ACS) therapy are poorly unoptimized. ACS therapy exerts a programming effect on fetal development, which may be associated with an increased risk of cardiovascular disease. Having demonstrated that low-dose steroid therapy is an efficacious means of maturing the preterm lung, we hypothesized that a low-dose steroid exposure would exert fewer adverse functional and transcriptional changes on the fetal heart.

LPCAT1 levels in the placenta, the maternal plasma and the fetal plasma do not predict fetal lung responses to glucocorticoids in a sheep model of pregnancy.

Introduction: Lysophosphatidylcholine acyltransferase 1 (LPCAT1) is important for saturated phosphatidylcholine (Sat-PC) production in the lung. Sat-PC is a critical component of pulmonary surfactant, which maintains low alveolar surface tension, facilitating respiration. Previous studies have reported an association between maternal and fetal LPCAT1 levels and neonatal lung function.

Assessment of synthetic red cell therapy for extremely preterm ovine fetuses maintained on an artificial placenta life-support platform.

Background: Artificial placenta therapy (APT) is an experimental care strategy for extremely preterm infants born at 21-24 weeks' gestation. In our previous studies, blood taken from the maternal ewe was used as the basis of priming solutions for the artificial placenta circuit. However, the use of maternal blood as a priming solution is accompanied by several challenges.

Direct administration of the non-competitive interleukin-1 receptor antagonist rytvela transiently reduced intrauterine inflammation in an extremely preterm sheep model of chorioamnionitis.

Background: Intraamniotic inflammation is associated with up to 40% of preterm births, most notably in deliveries occurring prior to 32 weeks' gestation. Despite this, there are few treatment options allowing the prevention of preterm birth and associated fetal injury. Recent studies have shown that the small, non-competitive allosteric interleukin (IL)-1 receptor inhibitor, rytvela, may be of use in resolving inflammation associated with preterm birth (PTB) and fetal injury.

Thoracic Empyema Secondary to Congenital Chylothorax in a 14-Month-Old Boy with Noonan Syndrome.

Thoracic empyema usually occurs as a complication of bacterial pneumonia, but in rare cases, it is caused by hematogenous dissemination secondary to nonpulmonary diseases. Congenital chylothorax or chylothorax in children is associated with maldevelopment of the lymphatic system, nonimmune hydrops fetalis, several syndromes including Down syndrome, Noonan syndrome, or Turner syndrome, a complication of thoracic surgery, right heart failure with high central venous pressure, or tumors. There are very few reports of empyema associated with preexisting chylothorax.

Diagnostic Specificity of Cerebral Magnetic Resonance Imaging for Punctate White Matter Lesion Assessment in a Preterm Sheep Fetus Model.

Recent studies, using magnetic resonance imaging (MRI) to assess white matter injury in preterm brains, increasingly recognize punctate white matter lesions (PWML) as the primary lesion type. There are some papers showing the relationship between the size and number of PWML and the prognosis of infants. However, the histopathological features are still unknown.

Variability in the efficacy of a standardized antenatal steroid treatment was independent of maternal or fetal plasma drug levels: evidence from a sheep model of pregnancy.

Background: Administration of antenatal steroids is standard of care for women assessed to be at imminent risk of preterm delivery. There is a marked variation in antenatal steroid dosing strategy, selection for treatment criteria, and agent choice worldwide. This, combined with very limited optimization of antenatal steroid use per se, means that treatment efficacy is highly variable, and the rate of respiratory distress syndrome is decreased to perhaps as low as 40%.

Successful use of an artificial placenta-based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation.

Background: Ex vivo uterine environment therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid.

Organ blood flow in response to infusion of arginine vasopressin in premature fetal sheep.

Background: Arginine vasopressin (AVP) infusion has been shown to be a useful strategy for the management of systemic perfusion failure in premature infants. Our objective was to determine the characteristics of the blood flow redistribution induced by AVP infusion in premature fetal sheep.

Methods: Nine sheep fetuses at 99 to 113 days of gestation were continuously infused with AVP.

Successful maintenance of key physiological parameters in preterm lambs treated with ex vivo uterine environment therapy for a period of 1 week.

Background: Extremely preterm infants born at the border of viability (22-24 weeks' gestation) have high rates of death and lasting disability. Ex vivo uterine environment therapy is an experimental neonatal intensive care strategy that provides gas exchange using parallel membranous oxygenators connected to the umbilical vessels, sparing the extremely preterm cardiopulmonary system from ventilation-derived injury.

Objective: In this study, we aimed to refine our ex vivo uterine environment therapy platform to eliminate fetal infection and inflammation, while simultaneously extending the duration of hemodynamically stable ex vivo uterine environment therapy to 1 week.

Gastric Invasive Micropapillary Carcinoma with Intestinal Phenotypes Harboring a TP53 R175H Mutation.

We report a case of gastric invasive micropapillary carcinoma (IMPC) in an 86-year-old female patient. She was admitted to our hospital with a chief complaint of bloody emesis. Upper gastrointestinal endoscopy found a gastric adenocarcinoma at the antrum.

A novel splice site mutation in the noncoding region of BRCA2: implications for Fanconi anemia and familial breast cancer diagnostics.

Fanconi anemia (FA) is a rare recessive disorder with chromosomal instability, congenital abnormalities, and a high cancer risk. The breast cancer susceptibility gene BRCA2 (FANCD1) is one of the 16 genes involved in this recessive disease. We have identified a novel mutation of the splice donor site of intron 1 in the noncoding region of BRCA2 in a Japanese FA family.

Simultaneous presentation of tubal and primary abdominal pregnancies following clomiphene citrate treatment.

Abdominal pregnancy is a rare condition that is potentially life-threatening for the mother. We present a case of simultaneous ectopic pregnancies (EPs) in the right fallopian tube and in the vesicouterine pouch. A 26-year-old woman had undergone prior ovulation induction with clomiphene citrate and human chorionic gonadotropin (hCG) at an outside hospital for unexplained infertility.