Maria Cristina Pintus

Neonatal onset of nephrogenic syndrome of inappropriate antidiuresis

This paper describes the manifestaton in a child of a new syndrome characterized by unusual, severe, persistent hyponatremia associated with hyposmolarity, euvolemia, inappropriately concentrated urine and elevated natriuresis. This is the fourth case of this syndrome reported to date, and the first to be reported in a neonate. The clinical features resemble those typically observed in patients with inappropriate antidiuretic hormone secretion, although high arginine vasopressin (AVP) levels are lacking. The findings led the authors to hypothesise a nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The previously described R137C gain-of-function mutation was detected by means of mutation analysis of the V2R gene. Our results indicate that NSIAD is already present during the neonatal period and that molecular analysis of the V2R receptor should therefore be carried out, in all newborns with prolonged euvolemic hyponatremia with hypo-osmolarity, high urinary sodium and normal/low or undetectable AVP levels.

Urinary metabolomics of bronchopulmonary dysplasia (BPD): preliminary data at birth suggest it is a congenital disease

Abstract Objective: Bronchopulmonary dysplasia (BPD) or chronic lung disease is one of the principal causes of mortality and morbidity in preterm infants. Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. The trigger cause of the disease comprehends the impairment of the alveolar development and the increased angiogenesis. Nevertheless, the molecular pathways characterizing the disease are still unclear. Therefore, the use of the metabolomics technique, due to the capability of identifying instantaneous metabolic perturbation, might help to recognize metabolic patterns associated with the condition. Methods: The purpose of this study is to compare urinary metabolomics at birth in 36 newborns with a gestational age below 29 weeks and birth weight <1500 g (very low birth weight – VLBW), admitted in Neonatal Intensive Care Unit (NICU) divided into two groups: the first group (18 cases) consisting of newborns who have not yet developed the disease, but who will subsequently develop it and the second group (18 controls) consisting of newborns not affected by BPD. Urine samples were collected within 24–36 h of life and immediately frozen at −80 °C. Results: The 1H-NMR spectra were analyzed using a partial least squares discriminant analysis (PLS-DA) model coupled with orthogonal Signal Correction. Using this approach it was possible with urine at birth to discriminate newborns that will be later have a diagnosis of BPD with a high statistics power. In particular, we found five important discriminant metabolites in urine in BPD newborns: lactate, taurine, TMAO, myoinositol (which increased) and gluconate (which decreased). Conclusion: These preliminary results seem to be promising for the identification of predictor’s biomarkers characterizing the BPD condition. These data may suggest that BPD is probably the result of an abnormal development (respiratory bud, vascular tree, hypodysplasia of pneumocytes) and could be considered a congenital disease (genetics plus intrauterine epigenetics). Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications.

Neonatal hyponatremia: differential diagnosis and treatment

Hyponatremia is very frequent in neonates, especially in VLBW. Recent data have shown that hyponatremia is not so benign as previously believed,and several clinical studies have indicated that preterms with mild to moderate chronic hyponatremia may experience poor growth and development retardation. The aim of this review is to present how to differentiate hypovolemic, euvolemic and hypervolemic hypernatremias, suggesting algorithms for practical management.

Introduction to embryonic and adult neural stem cells: from the metabolic circuits of the niches to the metabolome

Metabolomics has provided new insight into the biology that drives the phenotype of stem cells. During the recent years, metabolic circuits of embryonic and neural stem cells (NSCs) have been better elucidated. Many factors contribute to stem cell determination fate: metabolism, transcriptional signaling, epigenetics, extrinsic mechanisms such as short-range signals from the niche and humoral signals. The metabolism decides if a cell proliferates, differentiates or remains quiescent. Embryonic and adult NSCs share two features: they generate at least one daughter cell and can differentiate into specialized cells. NSCs use different pathways depending on their stage of differentiation: glycolysis is highest in proliferating stem cells and it is essential for stemness. Conversely, oxidative phosphorylation supports differentiated cells. Moreover, lipid metabolism maintains proliferation and neurogenesis; indeed, fatty acid oxidation and fatty acid synthesis represent a component of stem cell fate regulation. Proceedings of the 2 nd International Course on Perinatal Pathology (part of the 11 th International Workshop on Neonatology · October 26 th -31 st , 2015) · Cagliari (Italy) · October 31 st , 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

Multipotent stem cells of mother's milk

In recent years the presence of stem cells (hBSCs: human breastmilk-derived stem cells) and epithelial progenitors has been demonstrated in mother’s milk (MM). Stem cells present in samples of fresh MM exhibit a high degree of vitality and this makes possible the performance of cell cultures and to evaluate the differentiation capacity of the hBSCs. The most important datum that expresses the enormous potential of the use of MM stem cells is the presence of a cell population capable of differentiating into the three mesoderm, endoderm and ectoderm lines. The small number of studies and MM samples analyzed and the different sampling methods applied suggest standardization in the collection, analysis and culture of MM in future studies, in consideration of the well-known extreme variability of MM composition, also from the standpoint of cells. The analysis of literature data confirms the uniqueness of MM and its enormous potential. Proceedings of the 2 nd International Course on Perinatal Pathology (part of the 11 th International Workshop on Neonatology · October 26 th -31 st , 2015) · Cagliari (Italy) · October 31 st , 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

Stem/progenitor cells in the developing human cerebellum: an immunohistochemical study

The aim of this study was to analyze, by immunohistochemistry, the occurrence of stem/progenitor cells localized in the different niches of the developing human cerebellum. To this end, cerebellar samples were obtained from 3 fetuses and 3 newborns ranging, respectively, from 11 to 24 and from 30 to 38 weeks of gestation. Specimens were 10% formalin-fixed, routinely processed and paraffin-embedded; 3 μm-tick sections were immunostained with anti-SOX2 and PAX6 antibodies. Our study evidenced SOX2 and PAX6 immunoreactivity in precursors cells in all six developing human cerebella. SOX2 was expressed in precursors of different neural cell types, including Purkinje neurons, stellate cells, basket cells and Golgi cells. In the cerebellar cortex, SOX2 expression changed during gestation, being highly expressed from the 20th up to the 24th week, whereas at the 30th and at the 34th week SOX2 immunoreactivity was restricted to the Purkinje cell layer and the inner zone. Cerebellar human cortex was negative at the 38th week of gestation. PAX6 immunoreactivity was restricted to granule cell precursors in the external granule layer (EGL), being detected at all gestational ages. Our study indicates SOX2 and PAX6 as two useful markers of stem/progenitor cells that highlight the different germinative zones in the developing human cerebellum.

Stem/progenitor cells in the cerebral cortex of the human preterm: a resource for an endogenous regenerative neuronal medicine?

The development of the central nervous system represents a very delicate period of embryogenesis. Premature interruption of neurogenesis in human preterm newborns can lead to motor deficits, including cerebral palsy, and significant cognitive, behavioral or sensory deficits in childhood. Preterm infants also have a higher risk of developing neurodegenerative diseases later in life. In the last decade, great importance has been given to stem/progenitor cells and their possible role in the development and treatment of several neurological disorders. Several studies, mainly carried out on experimental models, evidenced that immunohistochemistry may allow the identification of different neural and glial precursors inside the developing cerebral cortex. However, only a few studies have been performed on markers of human stem cells in the embryonic period. This review aims at illustrating the importance of stem/progenitor cells in cerebral cortex during pre- and post-natal life. Defining the immunohistochemical markers of stem/progenitor cells in the human cerebral cortex during development may be important to develop an “endogenous” target therapy in the perinatal period. Proceedings of the 2 nd International Course on Perinatal Pathology (part of the 11 th International Workshop on Neonatology · October 26 th -31 st , 2015) · Cagliari (Italy) · October 31 st , 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordano

Urinary 1H-NMR Metabolomics in the First Week of Life Can Anticipate BPD Diagnosis

Despite the advancements in medical knowledge and technology, the etiopathogenesis of bronchopulmonary dysplasia (BPD) is not yet fully understood although oxidative stress seems to play a role, leading to a very demanding management of these patients by the neonatologist. In this context, metabolomics can be useful in understanding, diagnosing, and treating this illness since it is one of the newest omics science that analyzes the metabolome of an individual through the investigation of biological fluids such as urine and blood. In this study, 18 patients admitted to the Neonatal Intensive Care Unit of the Cagliari University Hospital were enrolled. Among them, 11 patients represented the control group and 7 patients subsequently developed BPD. A sample of urine was collected from each patient at 7 days of life and analyzed through 1H-NMR coupled with multivariate statistical analysis. The discriminant metabolites between the 2 groups noted were alanine, betaine, trimethylamine-N-oxide, lactate, and glycine. Utilizing metabolomics, it was possible to detect the urinary metabolomics fingerprint of neonates in the first week of life who subsequently developed BPD. Future studies are needed to confirm these promising results suggesting a possible role of microbiota and oxidative stress, and to apply this technology in clinical practice.