Human umbilical cord mesenchymal stromal cells as an adjunct therapy with therapeutic hypothermia in a piglet model of perinatal asphyxia.

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.

To be born twin: effects on long-term neurodevelopment of very preterm infants-a cohort study.

Objective: To examine the effect of twin birth on long-term neurodevelopmental outcomes in a cohort of Italian preterm infants with very low birth weight. Study design: We performed a retrospective cohort study on children born in a tertiary care centre. We included children born between 1 January 2007 and 31 December 2013 with a gestational age (GA) of ≤32 weeks and birth weight of <1,500 g. The infants born from twin pregnancies complicated by twin-to-twin transfusion syndrome and from higher-order multiple pregnancies were excluded. The children were evaluated both at 2 years corrected age and 5 years chronological age with Griffiths mental development scales revised (GMDS-R). The linear mixed effects models were used to study the effect of being a twin vs. being a singleton on GMDS-R scores, adjusting for GA, being born small for gestational age, sex, length of NICU stay, socio-economic status, and comorbidity score (CS) calculated as the sum of the weights associated with each of the major morbidities of the infants. Results: A total of 301 children were included in the study, of which 189 (62.8%) were singletons and 112 (37.2%) were twins; 23 out of 112 twins were monochorionic (MC). No statistically significant differences were observed between twins and singletons in terms of mean general quotient and subscales at both 2 and 5 years. No effect of chorionicity was found when comparing scores of MC and dichorionic twins vs. singletons; however, after adjusting for the CS, the MC twins showed lower scores in the hearing and language and performance subscales at 5 years. Conclusion: Overall, in our cohort of children born very preterm, twin infants were not at higher risk of neurodevelopmental impairment compared with singletons at pre-school age.

Red blood cell transfusions in preterm newborns and neurodevelopmental outcomes at 2 and 5 years of age.

BACKGROUND: Red blood cell (RBC) transfusion is often considered a life-saving measure in preterm neonates. However, it has been associated with detrimental effects on short-term morbidities and, recently, on brain development. The aim of the present study was to evaluate the association between RBC and long-term neurodevelopmental outcome in a cohort of preterm infants. MATERIALS AND METHODS: This retrospective cohort study was carried out in the period 2007-2013. Preterm infants with a gestational age (GA) ≤ 32 weeks and birthweight (BW) <1,500 g were included. Infants underwent Griffiths assessment at 24±6 months corrected age (CA) and at 5±1 years of age. We used a multivariate regression model to assess the association of RBC transfusions and long-term neurodevelopment after controlling for GA, being small for GA, major neonatal morbidities, and socio-economic status. We also evaluated the impact of early RBC administration (within the first 28 days of life) compared to those performed after the first month of life. RESULTS: We enrolled 644 preterm infants, among whom 54.3% were transfused during their stay in the neonatal intensive care unit (NICU). In infants with a longitudinal follow-up evaluation (n=360), each RBC transfusion was independently associated with a reduction in the Griffiths General Quotient (GQ) by -0.96 (p=0.002) at 24 months CA. Early RBC administration had the biggest impact, especially in children without brain lesions, where the reduction in Griffiths GQ for each additional transfusion was -2.12 (p=0.001) at 24 months CA and -1.31 (p=0.006) at 5 years of age, respectively. DISCUSSION: In preterm infants, RBC transfusions are associated with long-term neurodevelopmental outcome, with a cumulative effect. Early RBC administration is associated with a greater reduction in Griffiths scores. The impact of RBC transfusion on neurodevelopment is greater at 24 months CA, but persists, although to a lesser degree, at 5 years of age.

Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies.

Very preterm infants may manifest neurodevelopmental impairments, even in the absence of brain lesions. Pathogenesis is complex and multifactorial. Evidence suggests a role of early adversities on neurodevelopmental outcomes, via epigenetic regulation and changes in brain architecture. In this context, we focused on cumulative pain exposure which preterm neonates experience in neonatal intensive care unit (NICU). We systematically searched for: i) evidence linking pain with brain development and exploring the potential pathogenetic role of epigenetics; ii) preclinical research supporting clinical observational studies. Nine clinical neuroimaging studies, during neonatal or school age, mostly from the same research group, revealed volume reduction of white and gray matter structures in association with postnatal pain exposure. Three controlled animal studies mimicking NICU settings found increased cell death or apoptosis; nevertheless, eligible groups were limited in size. Epigenetic modulation (SLC6A4 promoter methylation) was identified in only two clinical trials. We call for additional research and, although knowledge gaps, we also point out the urgent need of minimizing painful procedures in NICUs.

Early detection of general movements trajectories in very low birth weight infants.

The aim of the study was to investigate General Movements'(GMs) neonatal trajectories and their association with neurodevelopment at three months corrected age (CA) in preterm infants. We conducted an observational, longitudinal study in 216 very low birth weight infants. GMs were recorded at 31 ± 1, 35 ± 1, 40 ± 1 weeks of postmenstrual age and at three months of corrected age (CA). More than 90% of infants showing neonatal trajectories with persistent Normal (N-N) or initial Poor Repertoire to Normal (PR-N) movements presented fidgety pattern at three months CA. On the contrary, fidgety movements were not detected in any infant with a trajectory of persistent Cramped-Synchronized (CS-CS) or an initial Poor-Repertoire to Cramped-Synchronized (PR-CS) movements. Trajectories with initial Normal to Poor-Repertoire (N-PR) or persistent Poor-Repertoire (PR-PR) movements showed an increased risk of having a non-normal Fidgety pattern compared with the N-N group (OR = 8.43, 95% CI: 2.26-31.45 and OR = 15.02, 95% CI: 6.40-35.26, respectively). These results highlight the importance to evaluate neonatal GMs' trajectory to predict infants' neurodevelopment. N-N or PR-N trajectories suggest normal short-term neurodevelopment, especially a lower risk of Cerebral Palsy; whereas findings of N-PR and PR-PR trajectories indicate the need for closer follow up to avoid delay in programming intervention strategies.

Unrecognised diaphragmatic hernia in a refugee child: an incidental diagnosis.

A 4-year-old boy from Syria was evaluated at the emergency department because of an upper airway viral illness. His physical examination showed a significant intensity reduction of all heart sounds in the absence of any other pathological signs. As the child was affected with Down's syndrome and had suffered thoracic and abdominal trauma because of bombardments, a diaphragmatic hernia was immediately suspected and was confirmed through a simple chest X-ray. A careful clinical examination is crucial in refugee children and adolescents, as several medical and surgical disorders could have escaped previously.

Lung disease recalling paraseptal emphysema in a patient with Goltz syndrome.

BACKGROUND: Goltz syndrome is a rare, genetic disorder mainly occurring in female patients. CASE PRESENTATION: The case presented here is, to the best of our knowledge, the first description of the occurrence of lung parenchymal alterations in a young female patient affected by Goltz syndrome. Although pulmonary involvement is not known in patients affected by X-linked Goltz syndrome, the case here described is related to the even rarer autosomal form of the disease, as in this case. It is thus conceivable that in such different genetic setting the involvement of lung parenchyma may be unveiled through atypical emphysematous lesions. CONCLUSION: This report suggested - for the first time time - a rationale for a lung function and imaging screening in patients affected by Goltz syndrome at least in its autosomal form.