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The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation. [ABSTRACT FROM AUTHOR]

Preterm birth is the leading cause of death in newborns and children. Despite advances in perinatology, immature infants continue to face serious risks such chronic respiratory impairment from bronchopulmonary dysplasia (BPD). Current treatment options are insufficient and novel approaches are desperately needed. In recent years stem cells have emerged as potential candidates to treat BPD with mesenchymal stem/stromal cells (MSCs) being particularly promising. MSCs originate from several stem cell niches including bone marrow, skin, or adipose, umbilical cord, and placental tissues. Although the first MSCs clinical trials in BPD are ongoing, multiple questions remain open. In this review, we discuss the question of the optimal cell source (live cells or cell products), route and timing of the transplantation. Furthermore, we discuss MSCs possible capacities including migration, homing, pro-angiogenesis, anti-inflammatory, and tissue-regenerative potential as well. [ABSTRACT FROM AUTHOR]

Introduction: Perinatal asphyxia (PA) is a major cause of neonatal mortality and morbidity. Research has shown that in rats fetal asphyxia (FA) can provoke neuroprotection against a subsequent more severe perinatal asphyctic insult. This is called fetal asphyctic preconditioning (PC). Our objective was to investigate alterations in the placental inflammatory phenotype associated with PC.Methods: FA was induced in the rat at embryonic day 17 by reversibly clamping the uterine circulation and PA was induced at birth by submersion of the uterine horns in a saline bath for 19 min. The effect of PC was studied by inducing FA at E17, followed by PA at E21. Placental TNF-α, IL-1β, IL-6 and IL-10 mRNA and protein levels were measured by qPCR and ELISA.Results: IL-1β mRNA increased in the labouring FA group, but IL-1β protein decreased after both FA and PA. In the PC group, IL-1β mRNA and protein levels were similar to controls. IL-6 protein increased 6 h after FA, however decreased 24 h after FA. IL-6 mRNA was higher in the labouring PA group. IL-10 protein decreased 24 h after FA. At birth, IL-10 mRNA increased in the PA group; however, IL-10 protein decreased in both the PA and the FA group. In the PC group, IL-10 mRNA and protein were similar to control levels.Discussion: Depleted protein concentrations of IL-10 and IL-1β after one single asphyctic insult were reversed after fetal asphyctic PC. In addition, PC placentas showed less up-regulation of IL-6 mRNA compared to the PA ones. This modulated placental inflammatory phenotype might contribute to the improved neonatal outcome showed after fetal asphyctic PC. [ABSTRACT FROM AUTHOR]

In recent years, translational research with various animal models has been helpful to answer basic questions about the effect of antenatal inflammation on maturation and development of the fetal lung and immune system. The fetal lung and immune systems are very plastic and their development can be conditioned and influenced by both endogenous and/or exogenous factors. Antenatal inflammation can induce pulmonary inflammation, leading to lung injury and remodeling in the fetal lung. Exposure to antenatal inflammation can induce interleukin-1α production, which enhances surfactant protein and lipid synthesis thereby promoting lung maturation. Interleukin-1α is therefore a candidate for the link between lung inflammation and lung maturation, preventing respiratory distress syndrome in preterm infants. Antenatal inflammation can, however, cause structural changes in the fetal lung and affect the expression of growth factors, such as transforming growth factor-beta, connective tissue growth factor, fibroblast growth factor-10, or bone morphogenetic protein-4, which are essential for branching morphogenesis. These alterations cause alveolar and microvascular simplification resembling the histology of bronchopulmonary dysplasia. Antenatal inflammation may also affect neonatal outcome by modulating the responsiveness of the immune system. Lipopolysaccharide-tolerance (endotoxin hyporesponsiveness/immunoparalysis), induced by exposure to inflammation in utero, may prevent fetal lung damage, but increases susceptibility to postnatal infections. Moreover, prenatal exposure to inflammation appears to be a predisposition for the development of adverse neonatal outcomes, like bronchopulmonary dysplasia, if the preterm infant is exposed to a second postnatal hit, such as mechanical ventilation oxygen exposure, infections, or steroids. [Copyright &y& Elsevier]

Abstract: Ureaplasma is an organism with low virulence and is a commensal of the lower genito-urinary tract in females. From here, it can gain entry in the amniotic fluid to cause inflammation in the amniotic compartment during pregnancy. Ureaplasma spp. are the most common organisms isolated from women with chorioamnionitis. Ureaplasma spp. are associated with increased risk for preterm labor and morbidity in the preterm neonate. However, there is some controversy regarding the importance of Ureaplasma in the pathogenesis of bronchopulmonary dysplasia (BPD). This article will review the microbiology of Ureaplasma, host innate immune responses, and the pathology of lung injury in animal models of Ureaplasma chorioamnionitis. We will review epidemiological studies of Ureaplasma and BPD in preterm infants and efficacy of antibiotics in preventing preterm labor and BPD. [Copyright &y& Elsevier]

Abstract: Background: Diagnosis of necrotizing enterocolitis (NEC), prevalent in premature infants, remains challenging. Enterocyte damage in NEC can be assessed by intestinal fatty acid–binding protein (I-FABP), with a sensitivity of 93% and a specificity of 90%. Numerous markers of inflammation are known, such as serum amyloid A (SAA) and fecal calprotectin. Purpose: The aim of the present study was to evaluate which combination of noninvasive measurement of inflammatory markers and I-FABP improves the diagnostic accuracy in neonates suspected for NEC. Methods: In 62 neonates with clinical suspicion of NEC (29 with final diagnosis of NEC), urinary I-FABP, urinary SAA, and fecal calprotectin levels were determined quantitatively. Diagnostic accuracy was calculated for the combinations I-FABP–SAA and I-FABP–fecal calprotectin, using a multivariable logistic regression model. Results: The combination of SAA and I-FABP did not increase the diagnostic accuracy of I-FABP. However, the combination of fecal calprotectin and I-FABP improved accuracy significantly. The combination of urinary I-FABP and fecal calprotectin measurement produced a sensitivity of 94%, a specificity of 79%, a positive likelihood ratio of 4.48, and a negative likelihood ratio of 0.08. Conclusion: The combination of noninvasive measurement of I-FABP and fecal calprotectin seems promising for diagnosing NEC at an early time point. Prospective analysis is required to confirm this finding and to evaluate better treatment strategies based on noninvasive measurement of I-FABP and calprotectin. [Copyright &y& Elsevier]

Abstract: Background: Preterm female infants have a survival advantage and enhanced lung development, which is an important determinant of preterm survival. Objective: Given the modulation of lung development by fetal exposure to infection/inflammation, we hypothesized that female fetuses have enhanced lung maturational responses to chorioamnionitis compared with male fetuses. Methods: Time-pregnant ewes received intra-amniotic injections with saline (n = 60) or lipopolysaccharide (LPS) at 2 days (n = 30) or 7 days (n = 45) before surgical delivery at 123 to 125 days of gestation (term: ∼147 days). We assessed inflammatory responses in bronchoalveolar lavage fluid and cord blood, lung maturation with pressure-volume curves, and lung structure. Results: Lung gas volume showed differences between the sexes after 2 days LPS (male 4.6 [1.2] mL/kg, female 7.7 [4.4] mL/kg; P = 0.02) and 7 days LPS (male 20.5 [9.3] mL/kg, female 27.0 [7.0] mL/kg; P = 0.01). The control group was not different by sex (male 8.0 [3.6] mL/kg, female 8.9 [3.9] mL/kg; P > 0.05). No difference in lung structure and in pulmonary and systemic inflammatory response was evident by sex. Conclusion: Preterm female sheep fetuses had increased lung gas volumes after exposure to LPS, without any detectable differences in fetal inflammatory responses. [Copyright &y& Elsevier]

Summary: Prenatal exposure of very low birth weight infants to chronic indolent chorioamnionitis with organisms such as mycoplasma and ureaplasma is frequent. Chorioamnionitis is inconsistently associated with changed risks of respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), probably because the diagnosis of chorioamnionitis does not quantify the extent or duration of the fetal exposures to infection and inflammation. The correlations between prenatal exposures and postnatal lung disease also are confounded by the imprecision of the diagnoses of RDS and BPD. In animal models, chorioamnionitis caused by pro-inflammatory mediators or live ureaplasma induces lung maturation, but also causes alveolar simplification and vascular injury. Intra-amniotic endotoxin administration also modulates the fetal innate immune system, resulting in maturation of monocytes to alveolar macrophages and the induction or paralysis of inflammatory responses depending on exposure history. Prenatal inflammation can have profound effects on the fetal lung and subsequent immune responses. [Copyright &y& Elsevier]

Background: In the inflamed lung of allergic asthma, an aberrant injury-repair response is accompanied by structural changes in the airway, known as airway remodeling. TGF-β and its downstream mediator connective tissue growth factor (CTGF) are playing a key role in these processes, resulting in irreversible airway remodelling. Objective: As histamine is a key mediator of allergic reactions, we investigated whether histamine is involved in airway remodeling. Methods: The effect of histamine and TGF-β1 on proliferation of lung fibroblast cells IMR-90 was studied by [3H]-thymidine proliferation assay. The regulation of CTGF by histamine and TGF-β1 in lung fibroblasts was analyzed by RT-PCR, real-time PCR, Western blot analysis, and promoter analysis and characterized by specific histamine-receptor antagonists. Results: Histamine and TGF-β1 enhanced proliferation of lung fibroblast cells IMR-90. Both induced CTGF mRNA and protein expression with different time kinetics. Whereas TGF-β1 induced maximal CTGF expression after 12 hours (347% ± 23%), histamine-induced maximal CTGF expression was lower and delayed (maximum expression of 204% ± 11% after 48 hours). Histamine and TGF-β1 stimulated the CTGF promoter and the TGF-β–response element in the CTGF promoter. The histamine-induced CTGF expression was mediated through the histamine receptor (HR1) and could be completely abolished by TNF-α. Conclusions: These findings demonstrate that histamine plays a potential role in the induction of airway remodeling mediated by the induction of lung fibroblasts proliferation and CTGF expression. Clinical implications: This mechanism could be important for prophylactic strategies aiming at airway remodeling and could be a new indication for antihistamine treatment. [Copyright &y& Elsevier]

Examines the effects of intra-amniotic endotoxin on fetal lung maturation. Improvement of postnatal lung function; Occurrence of fetal acidosis following intraperitoneal infusion; Injection of endotoxin into the amniotic cavity.

Background: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood.Objective: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings.Study Design: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation.Results: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs.Conclusion: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response. [ABSTRACT FROM AUTHOR]

Background: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure.Objective: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep.Study Design: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours.Results: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg.Conclusion: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus. [ABSTRACT FROM AUTHOR]

Background: Antenatal steroids are standard of care for cases of anticipated preterm labor to improve neonatal outcomes. However, steroids are potent drugs, and their use in pregnancy remains largely unoptimized.Objective: The objective of the study was to measure the maternofetal pharmacokinetics of constant, low-dose intravenous betamethasone phosphate infusions and correlate these data with the transcriptional effect exerted by subclinical betamethasone exposures on the ovine fetal lung.Study Design: Thirty-two ewes carrying a single fetus had surgery to catheterize fetal and maternal jugular veins at 116 days of gestation (term, 150 days). Animals were recovered for 2 days and then were randomized to receive 2 sequential maternal intravenous infusions of either (n = 4/group) of the following: 1) saline, 0.125, 0.04, or 0.0125 mg/kg betamethasone phosphate over 3 hours; or 2) saline, 0.25, 0.08, or 0.025 mg/kg betamethasone phosphate over 12 hours. Each infusion was separated by 2 days. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction and an ovine-specific microarray. Plasma betamethasone levels from time-course catheter samples were determined by mass spectrometry. Data were assessed for distribution, variance, and tested by an analysis of variance.Results: Betamethasone was detectable (>1 ng/mL) in fetal plasma only in animals randomized to 0.125 mg/kg 3 hour or 0.250 mg/kg 12 hour infusions. Fetal betamethasone half-lives were 1.7-2.8 times greater than maternal values. At maximum concentration, fetal plasma betamethasone levels were approximately 10% of maternal levels. Compared with saline control, all animals, other than those receiving 0.0125 mg/kg 3 hour betamethasone phosphate infusions, had evidence of dose-dependent glucocorticoid transcriptional responses in the fetal lung.Conclusion: Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority. [ABSTRACT FROM AUTHOR]

Objectives To test the hypothesis that fecal volatile organic compounds (VOCs) analysis by electronic nose (eNose) allows for early detection of necrotizing enterocolitis (NEC). Study design In 3 neonatal intensive care units, fecal samples of infants born at gestational age ≤30 weeks were collected daily, up to the 28th day of life. Included infants were allocated in 3 subgroups: NEC, sepsis, and matched controls. Three time windows were defined: (1) T −5,−4 (5 and 4 days before diagnosis); (2) T −3,−2 (3 and 2 days before diagnosis); and (3) T −1,0 (day before and day of diagnosis). Three subgroups were analyzed by eNose. Results Fecal VOC profiles of infants with NEC (n = 13) could significantly be discriminated from matched controls (n = 14) at T −3,−2 (area under the curve ± 95% CI, P value, sensitivity, specificity: 0.77 ± 0.21, P = .02, 83%, 75%); the accuracy increased at T −1,0 (0.99 ± 0.04, P ≤ .001, 89%, 89%). VOC profiles of infants with NEC were also significantly different from those with sepsis (n = 31) at T −3,−2 (0.80 ± 0.17, P = .004, 83%, 75%), but not at T −1,0 (0.64 ± 0.18, P = .216, 89%, 57%). Conclusions In this proof of principle study, we observed that fecal VOC profiles of infants with NEC could be discriminated from controls, from 2-3 days predating onset of clinical symptoms. Our observations suggest that VOC-profiling by eNose has potential as a noninvasive tool for the early prediction of NEC. [ABSTRACT FROM AUTHOR]

Objective: Ureaplasma colonization in the setting of polymicrobial flora is common in women with chorioamnionitis, and is a risk factor for preterm delivery and neonatal morbidity. We hypothesized that Ureaplasma colonization of amniotic fluid would modulate chorioamnionitis induced by Escherichia coli lipopolysaccharide (LPS). Study Design: Sheep received intraamniotic (IA) injections of media (control) or live Ureaplasma either 7 or 70 days before delivery. Another group received IA LPS 2 days before delivery. To test for interactions, U parvum–exposed animals were challenged with IA LPS, and delivered 2 days later. All animals were delivered preterm at 125 ± 1 day of gestation. Results: Both IA Ureaplasma and LPS induced leukocyte infiltration of chorioamnion. LPS greatly increased the expression of proinflammatory cytokines and myeloperoxidase in leukocytes, while Ureaplasma alone caused modest responses. Interestingly, 7-day but not 70-day Ureaplasma exposure significantly down-regulated LPS-induced proinflammatory cytokines and myeloperoxidase expression in the chorioamnion. Conclusion: Acute (7-day) U parvum exposure can suppress LPS-induced chorioamnionitis. [ABSTRACT FROM AUTHOR]

Objective: To accumulate available evidence regarding the association between antenatal inflammation and necrotizing enterocolitis (NEC). Study design: A systematic literature search was performed using Medline, Embase, Cochrane Library, ISI Web of Knowledge, and reference hand searches. Human studies published in English that reported associations between chorioamnionitis or other indicators of antenatal inflammation and NEC were eligible. Relevant associations were extracted and reported. Studies reporting associations between histological chorioamnionitis (HC) and NEC, HC with fetal involvement and NEC, and clinical chorioamnionitis and NEC were pooled in separate meta-analyses. Results: A total of 33 relevant studies were identified. Clinical chorioamnionitis was significantly associated with NEC (12 studies; n = 22 601; OR, 1.24; 95% CI, 1.01-1.52; P = .04; I 2 = 12%), but the association between HC and NEC was not statistically significant (13 studies; n = 5889; OR, 1.39; 95% CI, 0.95-2.04; P = .09; I 2 = 49%). However, HC with fetal involvement was highly associated with NEC (3 studies; n = 1640; OR, 3.29; 95% CI, 1.87-5.78; P ≤ .0001; I 2 = 10%). Selection based on study quality did not affect the results. No indications of publication bias were apparent. Multivariate analyses in single studies generally attenuated the reported associations. Several associations between other markers of antenatal inflammation and NEC are reported. Conclusion: Currently available evidence supports a role for antenatal inflammation in NEC pathophysiology. This finding emphasizes the need to further study the underlying mechanisms and evaluate potential interventions to improve postnatal intestinal outcomes. [Copyright &y& Elsevier]

Despite the use of intraoperative opioid analgesia, postoperative pain is often reported by patients undergoing craniotomies. Opioids also cause undesirable side effects in neurosurgical patients. Hence, the role of nonopioid analgesia has been explored for craniotomies in recent years. This systematic review evaluated evidence from randomized controlled trials (RCTs) comparing opioid and nonopioid analgesia during craniotomies regarding postoperative pain, recovery, and adverse events. Of the 10,459 records obtained by searching MEDLINE, Embase, and Web of Science databases, 6 RCTs were included. No difference was observed in pain scores between opioid and nonopioid analgesia at 1 and 24 hours after surgery: mean difference (MD), 1.11 units; 95% confidence interval [CI], −0.16 to 2.38, P = 0.09 and MD, −0.06 units; 95% CI, −1.14 to 1.01, P = 0.91, respectively. The time for first postoperative analgesic requirement was shorter with opioids but was not statistically significant (MD, −84.77 minutes; 95% CI, −254.65 to 85.11; P = 0.33). Postoperative nausea and vomiting (relative risk = 1.60; 95% CI, 0.96–2.66; P = 0.07) was similar but shivering (relative risk = 2.01; 95% CI, 1.09–3.71; P = 0.03) was greater in the opioid group than nonopioid group. There were no important differences in clinical outcomes between the groups in our review. The GRADE certainty of evidence was rated low for most outcomes. Available evidence does not suggest superiority of intraoperative nonopioid over opioid analgesia for postoperative pain in patients undergoing craniotomy. More studies are needed to firmly establish the role of nonopioid intraoperative analgesics as an alternative to opioids in this population. [ABSTRACT FROM AUTHOR]

Objective: We hypothesized that fetal innate immune responses to lipopolysaccharide-induced chorioamnionitis would alter postnatal systemic immune and airway responsiveness. Study Design: Ewes received intraamniotic injections with saline or lipopolysaccharide at 90, 100, and 110 days of gestation. Immune status and airway responsiveness were evaluated at term and at 7 weeks of age. Results: At term, lymphocytes, monocytes, and neutrophils were significantly increased (respectively, 24-fold, 127-fold, and 31,000-fold) in lungs and blood monocytes became Toll-like receptor 2 responsive after lipopolysaccharide exposures. Furthermore, CD4 and CD4/CD25 lymphocytes were increased in thymus and lymph nodes. At 7 weeks, airway reactivity decreased and concentrations of CD8 cytotoxic T lymphocytes changed in the lungs and thymus relative to controls. Conclusion: Early gestational lipopolysaccharide exposure increased leukocyte responsiveness at term. Decreased airway reactivity and changes in lymphocytes at 7 weeks postnatal demonstrate persistent effects of fetal exposure to LPS. [ABSTRACT FROM AUTHOR]

Objective: Regulatory T lymphocytes mediate homeostasis of the immune system and differentiate under the control of the transcription factor FoxP3 in the fetal thymus. We asked whether fetal inflammation caused by chorioamnionitis would modulate thymus development. Study Design: Fetal sheep were exposed to an intraamniotic injection of 10 mg lipopolysaccharide at 5 hours, 1 day, 2 days, or 5 days before delivery at 123 gestation days. Cord blood lymphocytes, plasma cortisol, and thymus weight were measured. Glucocorticoid receptor–, activated caspase-3–, Ki-67–, proliferating cell nuclear antigen–, nuclear factor-κB–, and FoxP3-positive cells were immunohistochemically evaluated in thymus. Results: Intraamniotic lipopolysaccharide exposure decreased the number of circulating lymphocytes by 40% after 1 day. Thymus-to-body weight ratios were reduced in all lipopolysaccharide groups by a maximum of 40% at 5 days. Lipopolysaccharide exposure modestly increased plasma cortisol concentration, increased nuclear factor-κB immunostaining in fetal thymus and reduced the number of FoxP3-positive cells by 40% at 1 day. Conclusion: Intraamniotic exposure to lipopolysaccharide induced thymic changes and influenced thymic FoxP3 expression. [Copyright &y& Elsevier]

Objective: The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants. Study Design: The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center. Results: In univariable analyses, HC without fetal involvement (n = 53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P < .05), whereas HC with fetal involvement infants (n = 68) had more necrotizing enterocolitis (9% vs 2%; P < .05), intraventricular hemorrhage (IVH) (25% vs 12%; P < .05), and neonatal mortality (19% vs 9%; P < .05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P < .05) and IVH (5% vs 39%; P < .01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05–0.93; P < .05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02–4.83; P < .05). Conclusion: In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome. [Copyright &y& Elsevier]

Objective: We quantified the impact of chorioamnionitis on both the white and gray matter structures of the preterm ovine central nervous system (CNS). Study Design: The CNS was studied at 125 days of gestation, either 2 or 14 days after the intraamniotic administration of 10 mg of lipopolysaccharide (LPS) (Escherichia coli) or saline. Apoptotic cells and cell types were analyzed in the brain, cerebellum, and spinal cord using flow cytometry. Results: Apoptosis and microglial activation increased in all regions with prolonged exposure to LPS-induced chorioamnionitis. Astrocytes were increased in the brain and cerebellum of LPS-exposed fetuses but not in the spinal cord. Mature oligodendrocytes decreased in the cerebral and cerebellar white matter, the cerebral cortex, caudate putamen, and hippocampus 14 days after LPS. Neurons in the cerebral cortex, hippocampus, and substantia nigra were reduced 14 days after LPS. Conclusion: Fetal inflammation globally but differentially affected the CNS depending on the maturational stage of the brain region. [Copyright &y& Elsevier]

Background: Antenatal pulmonary inflammation is associated with reduced risk for respiratory distress syndrome but with an increased risk for bronchopulmonary dysplasia (BPD) with impaired alveogenesis. Objective: We hypothesized that fetal systemic inflammation induced by intravenous (IV) lipopolysaccharide (LPS) would affect lung development in utero. Study Design: Twenty-one fetal sheep were instrumented (107 days gestational age). Control fetuses received saline (N = 12) and 9 in the study group received 100 ng of LPS IV 3 days after surgery. Animals were assessed for lung maturation and structure after 3 (N = 5) and 7 (N = 4) days. Results: Interleukin-6 concentration increased in the bronchoalveolar lavage more than 40-fold 3 days after LPS IV. Processing of pro-surfactant protein (SP)-B to mature SP-B and increased SP-B concentrations were shown 7 days after LPS IV. Deposition of elastin fibers at sites of septation was disturbed within 3 days after LPS IV. Conclusion: Lung maturation and disturbed lung structure occurred after short-term exposure to fetal inflammation and suggests new targeted therapies for BPD. [Copyright &y& Elsevier]

Objective: Macrophage migration inhibitory factor is a proinflammatory mediator of innate immunity, enhances cell growth, and plays a role in preterm delivery. We speculated that funisitis, reflecting fetal systemic inflammation, would be associated with higher concentrations of macrophage migration inhibitory factor in airways of extremely premature infants. Study Design: We measured macrophage migration inhibitory factor by enzyme linked immunosorbent assay in tracheobronchial aspirate fluid of 35 ventilated infants less than 30 weeks’ gestational age, throughout the first week of life. Three groups were distinguished histologically: chorioamnionitis, funisitis, and control. Results: Unexpectedly, funisitis was associated with significantly decreased macrophage migration inhibitory factor in tracheobronchial aspirate fluid on day 1 (P < .01) and levels remained lower than in the chorioamnionitis group thereafter. For the 35 patients in total, macrophage migration inhibitory factor steadily declined. Conclusion: Decreased macrophage migration inhibitory factor concentrations in airways of extremely premature infants with systemic fetal inflammation early in life might predispose them to pulmonary infection and interfere with maturation of the lung, contributing to adverse pulmonary outcome. [Copyright &y& Elsevier]

Background: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection. Aims: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model. Methods: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1–13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 106 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 106 IN PKH-labeled huMSCs were administered. Results: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration. Conclusions: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 106 cells/kg total dose) based on more rapid aEEG recovery, improved 31P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the association of adenomyosis with fertility, pregnancy and neonatal outcomes. An electronic search was conducted using the MEDLINE, PubMed and Cochrane databases up to April 2020. Seventeen observational studies were included. Adenomyosis was significantly associated with a lower clinical pregnancy rate (odds ratio [OR] 0.69; 95% confidence interval [CI] 0.51–0.94) and higher miscarriage rate (OR 2.17; 95% CI 1.25–3.79) after treatment with assisted reproductive technology (ART). The lower clinical pregnancy rate was more significant in the subgroup of patients with short down-regulation protocols. Similar associations were recorded after age adjustment. Adenomyosis was also significantly associated with an increased risk of pre-eclampsia, preterm delivery, Caesarean section, fetal malpresentation, small for gestational age infancy and post-partum haemorrhage, which was confirmed after correction for age and mode of conception. In conclusion, adenomyosis is associated with negative effects on fertility after ART. The potentially protective role of the ultra-long down-regulation protocols needs further evaluation in randomized controlled studies. Adenomyosis is also associated (independently of the mode of conception) with adverse pregnancy and neonatal outcomes. Proper counselling prior to ART and close monitoring of pregnancy in patients with adenomyosis should be recommended. [ABSTRACT FROM AUTHOR]

Introduction: The age of diagnosis of Huntington's disease (HD) varies among individuals with the same HTT CAG-repeat expansion size. We investigated whether early-life events, like perinatal insults or neurodevelopmental disorders, influence the diagnosis age.Methods: We used data from 13,856 participants from REGISTRY and Enroll-HD, two large international multicenter observational studies. Disease-free survival analyses of mutation carriers with an HTT CAG repeat expansion size above and including 36 were computed through Kaplan-Meier estimates of median time until an HD diagnosis. Comparisons between groups were computed using a Cox proportional hazard survival model adjusted for CAG-repeat expansion length. We also assessed whether the group effect depended on gender and the affected parent.Results: Insults in the perinatal period were associated with an earlier median age of diagnosis of 45.00 years (95%CI: 42.07-47.92) compared to 51.00 years (95%CI: 50.68-51.31) in the reference group, with a CAG-adjusted hazard ratio of 1.61 (95%CI: 1.26-2.06). Neurodevelopmental disorders were also associated with an earlier median age of diagnosis than the reference group of 47.00 years (95% CI: 43.38-50.62) with a CAG-adjusted hazard ratio of 1.42 (95%CI: 1.16-1.75). These associations did not change significantly with gender or affected parent.Conclusions: These results, derived from large observational datasets, show that perinatal insults and neurodevelopmental disorders are associated with earlier ages of diagnosis of magnitudes similar to the effects of known genetic modifiers of HD. Given their clear temporal separation, these early events may be causative of earlier HD onset, but further research is needed to prove causation. [ABSTRACT FROM AUTHOR]

Background: Data on long-term consequences of neonatal pain is limited.Aim: To assess whether perinatal factors, later pain experience and pain coping strategies are associated with altered pain threshold, pain tolerance and pain intensity in adolescents born preterm.Study Design: Observational, longitudinal study (Project on Preterm and SGA-infants, POPS-19).Subjects: We analyzed data of 412 adolescents at the age of 19years, who were born at a gestational age<32weeks or with a birth weight<1500g.Outcome Measures: Participants performed a standardized cold pressor test to assess pain threshold, tolerance and intensity. Furthermore, they completed a pain coping questionnaire (PCQ).Results: In univariate analysis, female gender and necrotizing enterocolitis (NEC) were associated with lower pain tolerance, indicated by reaching the ceiling time of 180s in ice water (females 19% vs males 29%, NEC 7% vs no NEC 25%). Female gender was associated with higher pain intensity (mean difference 0.58; 95%CI 0.21; 0.95) and lower pain threshold (log rank test p 0.007). In a multivariate Cox regression analyses, emotion focused avoidance pain coping style was significantly associated with lower pain threshold (hazard ratio HR 1.38; 95%CI 1.02; 1.87) and pain tolerance (HR 1.72; 95%CI 1.21; 2.42). NEC was significantly associated with lower pain threshold (HR 1.47; 95%CI 1.01; 2.14) and pain tolerance (HR 1.63; 95%CI 1.09; 2.41).Conclusion: In adolescence, maladaptive pain coping strategy was associated with lower pain threshold, pain tolerance and higher pain intensity. NEC was associated with altered pain response in adolescents born preterm. [ABSTRACT FROM AUTHOR]

Background: Data on long-term consequences of preterm birth on pain coping later in life are limited.Aim: To assess whether gestational age, birth weight and neonatal disease severity have effect on pain coping style in adolescents born preterm or with low birth weight.Study Design: Observational, longitudinal study (Project On Preterm and SGA-infants, POPS-19).Subjects: We analyzed data of 537 adolescents at the age of 19 years, who were born at a gestational age <32 weeks or with a birth weight <1500g.Outcome Measures: Participants completed the pain coping questionnaire (PCQ) that assesses pain coping strategies in three higher-order factors: approach ("to deal with pain"), problem-focused avoidance ("to disengage from pain") and emotion-focused avoidance ("expression of pain"). Furthermore, their pain coping effectiveness, pain controllability and emotional reactions to pain were assessed. All participants completed an IQ test.Results: Univariate analysis showed no significant correlation between length of stay, sepsis and necrotizing enterocolitis and any of the higher-order factors. Approach was only correlated with IQ. Problem-focused avoidance was, in the multiple regression analysis (including gestational age, IVH and IQ), only correlated with IQ. For emotion-focused avoidance (including birth weight, SGA, IVH, respiratory support and IQ) three independent predictors remained: IVH was positively correlated, while respiratory support and IQ were negatively correlated with emotion-focused avoidance.Conclusions: Early neonatal characteristics and neonatal disease severity have limited effect on pain coping style in adolescence. Higher IQ was associated with the use of adaptive coping strategies, while maladaptive strategies were used less. [ABSTRACT FROM AUTHOR]

Background Chest compressions (CC) during cardiopulmonary resuscitation (CPR) are the cornerstone of adult CPR protocols and are meant to restore circulation and improve outcome. Although adverse effects such as air-embolisms have been reported, these are rare and considered to be outweighed by beneficial effect. In newborns, however, the lung tissue is more fragile. Thus, the high intra-thoracic pressures resulting from CC may make the newborns more vulnerable for air-embolisms. Objectives We studied the postmortem prevalence of air-embolism in neonates that have received CPR. Methods Prospective cohort analysis of newborns receiving CC during CPR. CPR was performed by trained staff according to ILCOR guidelines, in a tertiary hospital. Air-embolisms were sought after using CT/MRI and autopsy. Results During a 61/2 year period (2007–2014), n = 56 newborns received CC. Newborns were resuscitated following severe perinatal hypoxia, or due to complications during NICU treatment. In n = 14 (25.0%) circulation could not be restored (mean CPR duration: 32.7 ± 15.2 min). Post-mortem CT/MRI was performed in n = 9, of whom n = 8 (88.9%) had air-embolisms. Autopsy was performed in n = 9. The air-embolisms could not be retraced on autopsy except for n = 1 patient. In patients with CPR resulting in restored circulation ( n = 42), no CT or MRI was performed for comparison due to radiation and/or hemodynamic instability. Cerebral ultrasound could not identify or exclude air-embolisms in this subgroup. Conclusions Post-mortem CT after prolonged resuscitation showed a high prevalence of intravascular air-embolism. Autopsy was not suited to detect air-embolism. The clinical importance of air-embolisms on the lethal outcome needs further research. [ABSTRACT FROM AUTHOR]

Abstract: Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is closely related to the development of white matter injury in the fetal brain. Large epidemiological studies support the link between FIRS and fetal brain injury with a clear association between the presence of in utero inflammation and neurodevelopmental complications such as cerebral palsy, autism and cognitive impairments later in life. Translational animal models of chorioamnionitis and fetal sepsis are essential in understanding the underlying pathophysiological mechanisms of fetal brain injury after exposure to intra-uterine inflammation. Concerning this aspect, ovine models have high translational value since neurodevelopment in sheep closely resembles the human situation. In this article, we will review clinical and experimental evidence for the link between FIRS and white matter injury in the fetal brain. With respect to experimental findings, we will particularly focus on the lessons learned from ovine models of chorioamnionitis and fetal sepsis. We also highlight two key players implied in the pathophysiology of white matter injury after in utero exposure to inflammation. [Copyright &y& Elsevier]

Abstract: Aim: To analyze quantitatively multi-channel amplitude-integrated EEG (aEEG) characteristics and assess regional differences. Methods: We investigated 40 preterm infants (postmenstrual age, PMA: range 27–37weeks) with normal follow-up at 24months of age, at a median postnatal age of 8days using 4-h EEG recordings according to the international 10–20 system reduced montage. Nine (3 transverse and 6 longitudinal) channels were selected and converted to aEEG registrations. For each aEEG registration, lower margin amplitude (LMA), upper margin amplitude (UMA) and bandwidth (UMA–LMA) were calculated. Results: In all channels PMA and LMA showed strong positive correlations. Below 32weeks of PMA, LMA was ≤5μV. Linear regression analysis showed a maximum LMA difference between channels of approximately 2 and 1μV at 27 and 37weeks of PMA, respectively. The lowest are LMA values in the occipital channel and the highest values are in centro-occipital channels. In the frontal, centro-temporal and centro-occipital channels, UMA and bandwidth changed with PMA. No differences in LMA, UMA and bandwidth were found between hemispheres. Skewness of LMA values strongly correlated with PMA, positive skewness indicating an immature brain (PMA≤32weeks) and negative skewness a maturing (PMA>32weeks) brain. Conclusions: We detected symmetric increase of aEEG characteristics, indicating symmetric brain maturation of the left and right hemispheres. Our findings demonstrate the clinical potential of computer-assisted analyses of aEEG recordings in detecting maturational features which are not readily identified visually. This may provide an objective and reproducible method for assessing brain maturation and long-term prognosis. [Copyright &y& Elsevier]

Summary: Progression of non-small-cell lung cancer (NSCLC) to metastasis is poorly understood. Two genetic approaches were used to evaluate the role of adherens junctions in a C-RAF driven mouse model for NSCLC: conditional ablation of the cdh1 gene and expression of dominant-negative (dn) E-cadherin. Disruption of E-cadherin caused massive formation of intratumoral vessels that was reversible in the early phase of induction. Vascularized tumors grew more rapidly, developed invasive fronts, and gave rise to micrometastasis. β-catenin was identified as a critical effector of E-cadherin disruption leading to upregulation of VEGF-A and VEGF-C. In vivo, lung tumor cells with disrupted E-cadherin expressed β-catenin target genes normally found in other endodermal lineages suggesting that reprogramming may be involved in metastatic progression. [Copyright &y& Elsevier]