Valéria Lima Passos

Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants

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.

Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study

BACKGROUND Inflammation, overhydration and elevated cardiac biomarkers are related to outcome in haemodialysis (HD) patients. Here, we explored the relationship between the body composition (BC), inflammation and cardiac biomarker concentrations in HD patients longitudinally. METHODS A total of 44 HD patients were followed for 6 months. BC was assessed by multifrequency bioimpedance (BIA). Serum concentrations of cardiac troponin T (cTnT), high-sensitive C-reactive protein (hsCRP), brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) were assessed at 2 monthly intervals. The longitudinal data analysis was conducted with a marginal model. RESULTS During the follow-up, the parameters describing the BC were highly predictive of both BNP and NT-proBNP and independent of gender, time, hsCRP and cTnT concentrations. The intracellular water (ICW)/body weight (BW) ratio (reflecting malnutrition) exerted a negative effect, whereas the extracellular water (ECW)/BW ratio (reflecting overhydration) had a positive effect on BNP and NT-proBNP concentrations. HsCRP and cTnT concentrations were significantly associated with each other. Furthermore, NT-proBNP concentrations were predictive of cTnT and hsCRP concentrations. CONCLUSIONS In the present study, we find a significant relation between BIA-derived BC parameters and natriuretic peptide concentrations. This relationship was independent of the cardiac history of the patient and suggests that the natriuretic peptide levels are to some degree modifiable by changing a patients fluid distribution. Moreover, cTnT, BNP, NT-proBNP and hsCRP were significantly related, showing a complex relation between overhydration, malnutrition, inflammation and cardiac biomarkers in dialysis patients.

IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study.

BackgroundElevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).MethodsEighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.ResultsRaised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.ConclusionOur findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.

Serum I-FABP as marker for enterocyte damage in coeliac disease and its relation to villous atrophy and circulating autoantibodies

Enterocyte damage is the hallmark of coeliac disease (CD) resulting in malabsorption. Little is known about the recovery of enterocyte damage and its clinical consequences. Serum intestinal fatty acid binding protein (I‐FABP) is a sensitive marker to study enterocyte damage.

Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

Early alterations of growth factor patterns in bronchoalveolar lavage fluid from preterm infants developing bronchopulmonary dysplasia

Chronic lung disease of prematurity (bronchopulmonary dysplasia; BPD) is characterized by an arrest in lung development. We hypothesized that early alterations in pulmonary expression of growth factors important for normal lung development would precede development of BPD. Bronchoalveolar lavage fluid (BALF) was obtained from ventilated preterm infants (n = 62) on postnatal d 0, 1, 3, and 7 and analyzed for total phospholipids (PL), VEGF, PDGF-BB, TGF-α and -β1, granulocyte macrophage colony stimulating factor (GM-CSF), and keratinocyte growth factor (KGF). Levels (Ln transformed) were compared between infants developing BPD and BPD-free survivors, adjusted for potential confounders. BPD was associated with higher overall GM-CSF (β (95% CI) = 0.69 (0.13;1.25); p < 0.05), lower overall latent TGF-β1 (β (95% CI) = −1.19 (−1.87, −0.39); p < 0.01) and total PL (β (95% CI) = −0.64 (−1.23, −0.05); p < 0.05), and lower d 0 and 3 levels of VEGF (mean difference (95% CI) = −1.75 (−2.72, −0.77), p < 0.001; and −1.18 (−2.30, −0.06), p < 0.05, respectively) and TGF-α (mean difference (95% CI) = −0.73 (−1.42, −0.04), p < 0.05; and −1.01 (−1.64, −0.38), p < 0.01, respectively). Day 0 VEGF levels had the highest predictive value for BPD (area under receiver operating characteristic curve = 0.87; p < 0.01). In conclusion, substantial alterations in BALF growth factor levels are present in infants developing BPD. An early imbalance in pulmonary growth factors may contribute to the developmental arrest of the lung seen in BPD.

Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep

BackgroundHypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI.MethodsPreterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis.ResultsGlobal HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability, hypomyelination and persistent suppressed brain function.ConclusionsOur data provided evidence that global HI in preterm ovine fetuses resulted in profound cerebral inflammation and mobilization of the peripheral innate immune system. These inflammatory responses were paralleled by marked injury and functional loss of the preterm brain. Further understanding of the interplay between preterm brain inflammation and activation of the peripheral immune system following global HI will contribute to the development of future therapeutic interventions in preterm HIE.

Atherosclerosis : contrast-enhanced MR imaging of vessel wall in rabbit model-comparison of gadofosveset and gadopentetate dimeglumine

PURPOSE To investigate the potential of gadofosveset for contrast material-enhanced magnetic resonance (MR) imaging of plaque in a rabbit model of atherosclerosis. MATERIALS AND METHODS All experiments were approved by the animal ethics committee. Thirty-one New Zealand White rabbits were included in one of four study groups: animals with atherosclerosis imaged with gadofosveset (n = 10) or gadopentetate dimeglumine (n = 7) and control animals imaged with gadofosveset (n = 7) or gadopentetate dimeglumine (n = 7). Aortic atherosclerosis was induced through endothelial denudation combined with a cholesterol-enriched diet. Control rabbits underwent a sham surgical procedure and received a regular diet. After 8 weeks, pre- and postcontrast T1-weighted MR images of the aortic vessel wall were acquired. Relative signal enhancement was determined with dedicated software. Statistical analysis was performed by using a generalized linear mixed model. Immunohistochemical staining with CD31 and albumin was used to assess microvessel density and the albumin content of the vascular wall. Group differences were analyzed by using a chi(2) test. Gadofosveset spatial distribution and content within the vessel wall were determined with proton-induced x-ray emission (PIXE) analysis. RESULTS Postcontrast signal enhancement was significantly greater for atherosclerotic than for control animals imaged with gadofosveset (P = .022). Gadopentetate dimeglumine could not enable discrimination between normal and atherosclerotic vessel walls (P = .428). PIXE analysis showed higher amounts of gadopentetate dimeglumine than gadofosveset in both atherosclerotic and normal rabbit aortas. Immunohistochemical staining revealed the presence of albumin and increased microvessel density in the vascular walls of atherosclerotic rabbits. CONCLUSION These results suggest that gadofosveset can be used to differentiate between atherosclerotic and normal rabbit vessel walls. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/250/3/682/DC1.

Endothelial Glycocalyx Structure in the Intact Carotid Artery: A Two-Photon Laser Scanning Microscopy Study

Background: The endothelial glycocalyx (EG) is the carbohydrate-rich luminal lining of endothelial cells that mediates permeability and blood cell-vessel wall interactions. To establish an atheroprotective role of the EG, adequate imaging and quantification of its properties in intact, viable, atherogenesis-prone arteries is needed. Methods: Carotid arteries of C57Bl6/J mice (n = 22) were isolated including the bifurcation, mounted in a perfusion chamber, and perfused with fluorescent lectin wheat germ agglutinin-fluorescein isothiocyanate. The EG was visualized through the vessel wall using two-photon laser scanning microscopy. An image quantification protocol was developed to assess EG thickness, which was sensitive to hyaluronidase-induced changes. Results: In the lesion-protected common carotid artery, EG thickness was found to be 2.3 ± 0.1 µm (mean ± SEM), while the surface area devoid of (wheat germ agglutinin-sensitive) EG was 8.9 ± 4.2%. Data from the external carotid artery were similar (2.5 ± 0.1 µm; 9.1 ± 5.0%). In the atherogenesis-prone internal carotid artery the EG-devoid surface area was significantly higher (27.4 ± 5.5%, p < 0.05); thickness at the remaining areas was 2.5 ± 0.1 µm. Conclusion: The EG can be adequately imaged and quantified using two-photon laser scanning microscopy in intact, viable mounted carotid arteries. Spatial EG differences could underlie atherogenesis.

Surface electrical stimulation in dysphagic parkinson patients: A randomized clinical trial

A new treatment for oropharyngeal dysphagia in Parkinsons disease was evaluated in the present study.