Antonios Marmarinos

Levels of bone collagen markers in preterm infants: relation to antenatal glucocorticoid treatment

Although the beneficial effects of antenatally administered glucocorticoids are well documented, data on the potential of adverse consequences are limited. The objective of this study was to determine the effects of antenatally administered glucocorticoids on biochemical markers of bone metabolism of 55 preterm infants with a gestational age of 24–34 weeks who were enrolled in the study. Neonates were divided into two groups according to antenatal exposure to corticosteroids. There were no significant differences between the groups in clinical characteristics and anthropometric variables. We studied blood levels of osteocalcin (OC), carboxy-terminal propeptide of type I procollagen (PICP), and carboxy-terminal telopeptide of type I collagen (ICTP) at the time of delivery, on postnatal day 10, and at 2 and 4 months of life. Comparing the groups, we found statistically significant reduction in PICP levels at birth in corticosteroid-exposed neonates (P < 0.05). The levels of bone markers increased progressively on the first days of life. There were no significant differences between groups in bone markers at 10 days or at 2 and 4 months of life. We found no significant difference for bone markers between groups of infants exposed to single or repeated maternal corticosteroid treatments. In summary, antenatal glucocorticoid treatments are suggested to have a negative impact on fetal bone formation as reflected by low PICP levels at birth. However, this negative effect on bone markers seems to be a temporary effect that subsides on the first days of life and afterward.

Serum Cystatin C in Pregnancies With Normal and Restricted Fetal Growth

The objective of this study was to investigate circulating levels of cystatin C (an important endogenous marker of renal function) in mothers, fetuses, and neonates from intrauterine growth–restricted (IUGR; characterized by impaired nephrogenesis) and appropriate-for-gestational-age (AGA) pregnancies. Serum cystatin C levels were measured by enzyme immunoassay in 40 parturients and their 20 IUGR (≤3rd customized centile, due to gestational pathology) and 20 AGA fetuses and neonates on postnatal day 1 (N1) and 4 (N4). Comparatively, creatinine and urea concentrations were determined in the same samples. Fetal cystatin C levels were higher in the AGA than the IUGR group (P = .001). In both groups, maternal cystatin C levels were lower than fetal (P < .001), N1 (P < .001), and N4 (P < .001) levels. Fetal levels were higher than N1 (P < .001) and N4 (P < .001), and N1 levels were higher than N4 (P = .007) ones. In both groups, no correlation existed between maternal and fetal levels, but positive correlations were found between cystatin C, creatinine, and urea levels in maternal and neonatal samples (in all cases, r ≥ 0.376 and P ≤ .045). Cystatin C levels did not correlate with gestational age and did not differ between males and females. Fetal cystatin C serum levels are lower in the IUGR group, significantly decrease after birth, and do not correlate with maternal levels in both groups. In addition, serum cystatin C levels positively correlate with respective creatinine and urea levels in the perinatal period.

Insulin-Like Growth Factor (IGF)-I and Insulin in Normal and Growth-Restricted Mother/Infant Pairs

Insulin-like growth factor (IGF)-I and insulin are essential for fetal growth. We investigated perinatal changes of both factors in 40 mothers and their 20 appropriate-for-gestational-age (AGA) and 20 intrauterine-growth-restricted (IUGR) fetuses and neonates on day 1 (N1) and day 4 (N4) postpartum. Fetal and N1, but not N4, IGF-I levels were increased in AGA (P < .001 and P = .037, resp.). N1 insulin levels were lower in IUGR (P = .048). Maternal, fetal, and N1 IGF-I, and fetal insulin levels positively correlated with customized centiles (r = .374, P = .035, r = .608, P < .001, r = .485, P = .006, and r = .654, P = .021, resp.). Female infants presented elevated fetal and N4 IGF-I levels (P = .023 and P = .016, resp.). Positive correlations of maternal, fetal, and neonatal IGF-I levels, and fetal insulin levels with customized centiles underline implication of both hormones in fetal growth. IUGR infants present gradually increasing IGF-I levels. Higher IGF-I levels are documented in females.

Differential expression of cord blood neurotrophins in gestational diabetes: the impact of fetal growth abnormalities

Abstract Objective: Gestational diabetes mellitus (GDM) may induce fetal macrosomia or growth restriction and is associated with later offspring neurodevelopmental disorders. We aimed to determine whether neurotrophins brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-4 (NT-4) are differentially expressed in cord blood samples at birth in large-for-gestational-age (LGA), intrauterine-growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) offspring of diabetic mothers, as compared to AGA controls from non-diabetic mothers. Methods: BDNF, NGF and NT-4 concentrations were prospectively determined in 80 cord blood samples from LGA (n = 15), IUGR (n = 12) and AGA (n = 33) diabetic, as well as from AGA normal (controls, n = 20) singleton full-term pregnancies. Results: Fetal BDNF concentrations considerably decreased in GDM, as compared with normal pregnancies [(b = −2.836, 95%CI −5.067 to (−0.604), p = 0.013)] and were higher in females (b = 2.298, 95%CI 0.357–4.238, p = 0.021). Cord blood NGF concentrations were lower in IUGR than AGA infants (p = 0.038). Conclusions: BDNF is down-regulated in the fetus exposed to GDM, independently of the fetal growth pattern, probably representing a candidate mechanism underlying the association between maternal diabetes and later psychopathology. IUGR fetuses born to diabetic mothers present with NGF deficiency, which may contribute to their long-term neurodevelopmental sequelae. Gender-dependent differences in fetal BDNF may partly explain the higher prevalence of adverse neurodevelopmental outcomes following brain insults in male infants.

The potential role of the lectin pathway of complement in the host defence of full-term intrauterine growth restricted neonates at birth

Objective: To prospectively investigate the potential role of the lectin pathway of complement in intrauterine-growth-restriction (IUGR, associated with impaired immunocompetence and increased risk for neonatal infections), by determining cord blood concentrations of mannose-binding lectin (MBL), H-ficolin and L-ficolin (important mediators of neonatal innate immunity) in IUGR and appropriate for gestational age (AGA) pregnancies. Furthermore, we aimed to describe correlations among cord blood MBL, H- and L-ficolin concentrations and with several demographic parameters of the infants at birth. Methods: Serum MBL, H- and L-ficolin concentrations were determined by ELISA in 154 mixed arteriovenous cord blood samples from IUGR (n = 50) and AGA (n = 104) singleton full-term infants. Results: Cord blood MBL concentrations were significantly lower in IUGR cases than AGA controls (p = 0.029). No differences in cord blood H- and L-ficolin concentrations were observed between groups. In the IUGR group, cord blood MBL concentrations negatively correlated with respective L-ficolin ones (r = −0.442, p = 0.001). Conclusions: The relatively decreased MBL expression in IUGR fetuses at term could possibly contribute to IUGR-associated neonatal immunodeficiency, predisposing to increased susceptibility to infections. The negative correlation between MBL and L-ficolin concentrations in the IUGR group might suggest an underlying immune variation and needs to be further investigated.

Calprotectin in human cord blood: relation to perinatal parameters and restricted fetal growth.

Abstract Objective: To determine cord blood levels of calprotectin, a protein that is increased in inflammatory states and released by activated neutrophils has apoptosis-inducing activity. Materials and methods: Cord-blood calprotectin concen-trations were determined in intrauterine-growth-restricted (IUGR, usually associated with increased neutrophil activation and apoptosis, n=50) and appropriate-for-gestational-age (AGA, n=110) single full-term pregnancies, and were correlated with perinatal demographic parameters. Results: No significant differences exists between the IUGR and AGA groups, implying that calprotectin at birth does not reflect increased neutrophil activation and apoptosis expected in IUGR. However, in IUGRs, calprotectin concentrations increased with every gestational week [b=45.3, 95% confidence interval (CI): 13.5–77.1, P=0.006], suggesting concomitant up-regulation of neutrophil activation and apoptosis. A combined group showed significantly decreased calprotectin concentrations in cesarean sections [b=–74.5, 95% CI: –115.2–(–33.9), P<0.001], pointing to excessive inflammatory response in vaginal deliveries. Finally, birth weight, customized centile, gender, maternal age and parity do not impact on cord blood calprotectin concentrations. Conclusions: Cord blood calprotectin concentrations at term are independent of intrauterine growth, gender, parity and maternal age and probably do not reflect the increased neutrophil activation and excessive apoptosis expected in IUGR.

Novel bioactive substances in human colostrum: could they play a role in postnatal adaptation?

Abstract Objective: To determine maternal colostrum/serum concentrations of the bioactive substances irisin, adropin and copeptin and investigate their association with several perinatal parameters and pathologic conditions during pregnancy. Methods: In a cohort of 81 mothers with full-term deliveries, colostrum/serum concentrations of irisin, adropin and copeptin were prospectively evaluated by ELISA on Day 3–4 postpartum. Results: Copeptin and adropin were detectable in human colostrum at higher, while irisin at lower concentrations than in maternal serum (p < 0.001 in all cases). Colostrum adropin and copeptin concentrations positively correlated with maternal serum ones (r = 0.421, p < 0.001 and r = 0.304, p = 0.006, respectively). Conclusions: Irisin, adropin and copeptin are present in colostrum and we speculate that they may be implicated in postnatal adaptation with respect to thermoregulation, vascular adaptation, glucose metabolism, lung function and fluid homeostasis. These findings may possibly enhance the necessity for early breastfeeding, particularly of infants born by cesarean section, who are prone to hypothermia, breathing disorders and dehydration.

Comparing calculated LDL-C with directly measured LDL-C in healthy and in dyslipidemic children.

BACKGROUND LDL-C is one of the strongest markers for atherosclerosis and therapeutic decisions in children are based on its levels. Friedewald formula (FF) which is usually used for the calculation of LDL-C (cLDL-C); and Anandarajas formula (AF) may under- or overestimate actual levels. OBJECTIVE To compare cLDL-C with directly measured LDL-C (dLDL-C) as a screening tool and to evaluate dyslipidemic children. METHODS The study population consisted of 1005 children, 2-18years, 688 of whom underwent lipid screening in a regular check-up (group A); and 317 were dyslipidemic (LDL-C ≥130mg/dl) (group B). A fasting serum lipid profile was assessed. LDL-C was measured using a homogenous assay and was calculated using FF and AF. RESULTS Each method of calculating LDL-C was highly correlated to dLDL-C. Using FF, cLDL-C was lower than dLDL-C in 75.6% (group A) and in 77.3% (group B) of children; the mean difference was significant in dyslipidemic group. Moreover, in group B, 25% of children with boundary high and 12% with high dLDL-C would be misclassified. Using AF, LDL-C was higher than dLDL-C; the mean difference was significant in group A. Based on cLDL-C, 52% of group A with borderline dLDL-C and 27.5% of group B children with boundary high dLDL-C would be considered as dyslipidemic and eligible for medication respectively. CONCLUSIONS Comparing two methods of calculated LDL-C with directly measured LDL-C. FF was more accurate as a screening tool while AF was more accurate in the evaluation and follow-up of the dyslipidemic group.

miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

Background:Despite the favourable survival rates of childhood acute lymphoblastic leukaemia (ALL), a significant number of patients present resistance to antileukaemic agents and dismal prognosis. In this study, we analysed miR-125b expression in childhood ALL and evaluated its clinical utility for patients treated with Berlin–Frankfurt–Münster (BFM) protocol.Methods:The study included 272 bone marrow specimens obtained on diagnosis and on BFM day 33 from 125 patients and 64 healthy children. Following extraction, RNA was polyadenylated and reverse transcribed. miR-125b levels were quantified by quantitative PCR. Cytogenetics, immunohistotype and MRD were analysed according to international guidelines.Results:Downregulated miR-125b levels were detected in childhood ALL patients and correlated with adverse prognosis. Following BFM induction, miR-125b levels were significantly increased, however, elevated day 33/diagnosis miR-125b ratio was associated with unfavourable disease features. Loss of miR-125b during diagnosis and higher day 33/diagnosis ratio were correlated with stronger risk for disease short-term relapse and patients’ worse survival. Moreover, multivariate regression models highlighted the independent prognostic value of miR-125b for childhood ALL. Finally, the combination of miR-125b with clinically used disease markers clearly enhanced the prediction of patients’ resistance to BFM chemotherapy.Conclusions:miR-125b significantly improves the prognosis of childhood ALL patients’ outcome under BFM treatment.

Influence of hypercholesterolemia on serum antibodies against oxidized LDL in children and adolescents

The oxidation of low‐density lipoprotein (LDL; oxLDL) appears to play a key role in the early development of atherosclerosis. Increased serum antibodies against the oxLDL (anti‐oxLDL antibodies) have been found in adults with atherosclerotic disease, as well as in healthy adults. The clinical significance and its precise role (atherogenic or atheroprotective), however, have not yet been clarified. This aim of this study was therefore to evaluate anti‐oxLDL antibodies in healthy children and adolescents with and without hypercholesterolemia.