Giovanni Ottonello

Metabolomics in newborns with intrauterine growth retardation (IUGR): urine reveals markers of metabolic syndrome

To date, we have little knowledge on the overall metabolic status of neonates with intrauterine growth retardation (IUGR). In the last few years, the analysis of metabolomics has assumed an important clinical role in identifying “disorders” in the metabolic profile of patients. The aim of this work has been to analyze the urine metabolic profiles of neonates with IUGR and compare them with controls to define the metabolic patterns associated with this pathology. To our knowledge, this is the first study of metabolomics performed on neonates with IUGR. Recruited for the study were 26 neonates with IUGR diagnosed in the neonatal period and with weight at birth below the 10th percentile and 30 neonates of proper gestational weight at birth (controls). In the first 24 hours (prior to feeding) (T1) and about 4 days after birth (T2), a urine sample was taken non-invasively from each neonate. The samples were then frozen at −80°C up to the time of the analysis by proton nuclear magnetic resonance spectroscopy (1H-NMR). The data contained in the NMR spectra obtained from the single samples were statistically analyzed using the Principal Components Analysis and the Partial Least Squares-Discriminate Analysis. By means of a multivariate analysis of the NMR spectra obtained, it was possible to highlight the differences between the two groups (IUGRs and controls) owing to the presence of different metabolic patterns. The discriminants in the urine metabolic profiles derived essentially from significant differences in certain metabolites such as: myo-inositol, sarcosine, creatine and creatinine. The metabolomic analysis showed different urine metabolic profiles between neonates with IUGR and controls and made it possible to identify the molecules responsible for such differences.

Physiopathology of intrauterine growth retardation: from classic data to metabolomics

It is well know that adverse conditions during intrauterine life, such as intrauterine growth restriction (IUGR), can result in permanent changes in the physiology and metabolism of the newborn, which in turn leads to an increased risk of disease in adulthood (fetal origin of adult disease hypothesis). In the first part of this review the epidemiological studies in which a correlation between low birth weight and chronic pathologies in adulthood was observed are reported. The second part of the review is focused on metabolomics studies that have revealed an altered metabolism in IUGR patients compared to controls. Together with more classic biomarkers of IUGR, such as endothelin-1, leptin, protein S100B and visfatin, the new holistic metabolomics approach has assumed a crescent role in the identification of disorders in the neonatal metabolic profile, determined by the interconnection of the different processes.

Metabolomics in paediatric respiratory diseases and bronchiolitis

The metabolic study of an organism may make it possible to monitor, through the metabolites,the physiology and/or pathology of the organism itself. Metabolomics, in the strictest sense, “the set of metabolites, the final products of the genetic expression”. Most clinical chemistry tests available today rely on old technologies that measure only a single chemical in blood, urine or other biofluids, and these tests are neither sensitive nor specific for any particular disease. Metabolomics offers a holistic approach to systems medicine, with the promise to enhance clinical chemistry diagnostics in several pathologic conditions. The present review covers the application of clinical metabolomics in three different areas of respiratory diseases in pediatrics: asthma, pneumonia and bronchiolitis. Comparison between two 1H-NMR urine spectra by two bronchiolitis patients are also presented.

Soluble CD14 subtype (sCD14-ST) presepsin in critically ill preterm newborns: preliminary reference ranges

Soluble CD14 subtype (sCD14-ST), also named presepsin, is a 13 kDa truncated form of soluble CD14 (sCD14), consisting of 64 amino acid residues. Systemic inflammation and sepsis are characterized by an early, significant increase in sCD14-ST presepsin blood concentration and thus, this small polypeptide has been proposed as a novel, reliable biomarker for the management of sepsis. We enrolled twenty-six consecutive non-septic preterm newborns with gestational age (GA) between 26 and 36 weeks) admitted to NICU after the first day of life for various severe diseases. sCD14-ST presepsin was measure on whole blood samples by a rapid commercial available chemiluminescent enzyme immunoassay (CLEIA) based on a non-competitive CLEIA. The mean sCD14-ST presepsin blood level in 26 preterm newborns was 643.1 ng/L, with a standard deviation (SD) of 303.8 ng/L; the median value was 578 ng/L. Our results clearly suggest no correlation between GA and sCD14-ST presepsin blood level between 26 and 36 weeks and thus it is reasonable to adopt a unique reference range for preterm newborns.

Metabolomics in Adult and Pediatric Nephrology

Metabolomics, the latest of the “omics” sciences, has a non-selective approach and can thus lead to the identification of all the metabolites (molecules < 1 kDa) in a biological system. The metabolomic profile can be considered the most predictive phenotype capable of evaluating epigenetic modifications determined by external factors. It is so close to the phenotype as to be considered the phenotype itself in its unique individuality (fingerprinting), both in health (phenome), and disease (diseasome). Urine, compared to other biological liquids, has the advantage of being a complex fluid with many components, including intermediate metabolites. Metabolomics may thus play a role in the study of different kidney diseases and overcome diagnostic difficulties. We shall present the studies that to our knowledge have been published on Nephrology and Pediatric Nephrology. Some are experimental while others are clinical. We have not considered carcinomas and transplantations. Although scarce, the data on adults and the very few ones in pediatrics are quite interesting. Further studies on kidneys are needed to determine the practical clinical impact of metabolomics in kidney renal pathologies. The “multiplatform” “omic” study of urine and namely metabolomics can contribute to improving early diagnosis and the outcome of kidney diseases.

Metabolomics and fetal-neonatal nutrition: between "not enough" and "too much".

Metabolomics is a new analytical technique defined as the study of the complex system of metabolites that is capable of describing the biochemical phenotype of a biological system. In recent years the literature has shown an increasing interest in paediatric obesity and the onset of diabetes and the metabolic syndrome in adulthood. Some studies show that fetal malnutrition, both excessive and insufficient, may permanently alter the metabolic processes of the fetus and increase the risk of future chronic pathologies. At present then, attention is being focused mainly on the formulation of new hypotheses, by means of metabolomics, concerning the biological mechanisms to departure from fetal-neonatal life that may predispose to the development of these diseases.

Urinary metabolomics (GC-MS) reveals that low and high birth weight infants share elevated inositol concentrations at birth.

Abstract Objective: Metabolomics is a new “omics” platform aimed at high-throughput identification, quantification and characterization of small-molecule metabolites. The metabolomics approach has been successfully applied to the classification different physiological states and identification of perturbed biochemical pathways. The purpose of the current investigation is the application of metabolomics to explore biological mechanisms which may lead to the onset of metabolic syndrome in adulthood. Methods: We evaluated differences in metabolites in the urine collected within 12 h from 23 infants with IUGR (IntraUterine Growth Restriction), or LGA (Large for Gestational Age), compared to control infants (10 patients defined AGA: Appropriate for Gestational Age). Urinary metabolites were quantified by GC-MS and used to highlight similarities between the two metabolic diseases and identify metabolic markers for their predisposition. Quantified metabolites were analyzed using a multivariate statistics coupled with receiver operator characteristic curve (ROC) analysis of identified biomarkers. Results: Urinary myo-inositol was the most important discriminant between LGA + IUGR and control infants, and displayed an area under the ROC curve = 1. Conclusion: We postulate that the increase in plasma and consequently urinary inositol may constitute a marker of altered glucose metabolism during fetal development in both IUGR and LGA newborns.

Soluble CD14 subtype (sCD14-ST) presepsin in premature and full term critically ill newborns with sepsis and SIRS

Neonatal sepsis still remains a major cause of morbidity and mortality in neonatal intensive care unit (NICU). Recently, soluble CD14 subtype (sDC14-ST) also named presepsin, was proposed as an effective biomarker for diagnosing, monitoring, and assessing the risk of neonatal sepsis and septic shock. The aim of this study was to investigate the diagnostic accuracy of sCD14-ST presepsin in diagnosing neonatal bacterial sepsis and in discriminating non-bacterial systemic inflammatory response syndrome (SIRS) from bacterial sepsis. This study involved 65 critically ill full-term and preterm newborns admitted to the neonatal intensive care unit (NICU), divided into three groups: 25 newborns with bacterial neonatal sepsis (group A); 15 newborns with a diagnosis of non-bacterial SIRS and with no localizing source of bacterial infection (group B); and 25 babies with no clinical or bacteriological signs of systemic or local infection receiving routine NICU care, most of them treated with phototherapy for neonatal jaundice (group C). A total of 102 whole blood samples were collected, 40 in group A, 30 in group B and 32 in group C. In 10 babies included in group A, sCD14-ST presepsin was also measured in an additional second blood sample collected 3 days after the start of antibiotic treatment. sCD14-ST presepsin was measured by a commercially available chemiluminescent enzyme immunoassay (CLEIA) optimized on an automated immunoassay analyzer. Statistical analysis was performed by means of MedCalc® statistical package; receiver operating characteristic (ROC) analysis was computed, and the area under the ROC curve (AUC) was used to evaluate the ability of sCD14-ST to discriminate neonatal bacterial sepsis from non-bacterial SIRS. Blood sCD14-ST presepsin levels were found significantly higher in bacterial sepsis when compared with controls (p<0.0001); similarly, they were higher in non-bacterial SIRS when compared with controls (p<0.0001). However, no statistically significant difference was found between bacterial sepsis and non-bacterial SIRS (p=0.730). In our population, CRP and sCD14-ST did not correlate with each other. ROC analysis revealed that sCD14-ST presepsin has an area under the curve (AUC) of 0.995 (95% C.I.: 0.941-1.00) greater than that of CRP (0.827; 95% C.I.: 0.72-0.906). Similarly, in the group of babies with non-infectious SIRS, sCD14-ST AUC was greater than CRP AUC (0.979; 95% C.I.: 0.906-0.999 versus 0.771; 95% C.I.: 0.647-0.868). In controls, preliminary reference intervals for sCD14-ST ranged 223.4-599.7 ng/L, being significantly different from those previously published elsewhere. In conclusion, sCD14-ST presepsin could be introduced in clinical practice as a diagnostic tool for improving the management of neonatal sepsis and non-bacterial SIRS.

Isolated 'sign of the horns': a simple, pathognomonic, prenatal sonographic marker of Crisponi syndrome.

The case of a patient presenting with Crisponi syndrome recently hospitalized at our institution is described. During pregnancy a diagnosis of this syndrome was hypothesized following sonographic observation of the fetus with the hands showing ‘the sign of the horns’. Such a finding, if isolated, as in our case, may represent a simple, pathognomonic sonographic marker of Crisponi syndrome.

A case of neonatal urosepsis with multifocal osteoarthritis: could ultrasonography change the clinical course?

An eleven-day boy neonate with a fetal anamnesis of grade 1 bilateral hydronephrosis according to the grading of the Society for Fetal Urology (SFU), came to our attention for an acute osteoarthritis secondary to urosepsis. In the urological follow-up, a severe bilateral vesico-ureteral reflux (VUR) was diagnosed. An early post-natal, reno-vesicle ultrasound evaluation could have changed the clinical course of our patient.