Antioxidant Protects against Increases in Low Molecular Weight Hyaluronan and Inflammation in Asphyxiated Newborn Pigs Resuscitated with 100% Oxygen

BACKGROUND: Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation. METHODS & PRINCIPAL FINDINGS: Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFα and IL1ß were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFα and IL1ß expression. CONCLUSIONS & SIGNIFICANCE: Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFα and IL1ß expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation

Parental and infant characteristics and childhood leukemia in Minnesota

<p>Abstract</p> <p>Background</p> <p>Leukemia is the most common childhood cancer. With the exception of Down syndrome, prenatal radiation exposure, and higher birth weight, particularly for acute lymphoid leukemia (ALL), few risk factors have been firmly established. Translocations present in neonatal blood spots and the young age peak of diagnosis suggest that early-life factors are involved in childhood leukemia etiology.</p> <p>Methods</p> <p>We investigated the association between birth characteristics and childhood leukemia through linkage of the Minnesota birth and cancer registries using a case-cohort study design. Cases included 560 children with ALL and 87 with acute myeloid leukemia (AML) diagnoses from 28 days to 14 years. The comparison group was comprised of 8,750 individuals selected through random sampling of the birth cohort from 1976–2004. Cox proportional hazards regression specific for case-cohort studies was used to compute hazard ratios (HR) and 95% confidence intervals (CIs).</p> <p>Results</p> <p>Male sex (HR = 1.41, 95% CI 1.16–1.70), white race (HR = 2.32, 95% CI 1.13–4.76), and maternal birth interval ≥ 3 years (HR = 1.31, 95% CI 1.01–1.70) increased ALL risk, while maternal age increased AML risk (HR = 1.21/5 year age increase, 95% CI 1.0–1.47). Higher birth weights (>3798 grams) (HRALL = 1.46, 1.08–1.98; HRAML = 1.97, 95% CI 1.07–3.65), and one minute Apgar scores ≤ 7 (HRALL = 1.30, 95% CI 1.05–1.61; HRAML = 1.62, 95% CI 1.01–2.60) increased risk for both types of leukemia. Sex was not a significant modifier of the association between ALL and other covariates, with the exception of maternal education.</p> <p>Conclusion</p> <p>We confirmed known risk factors for ALL: male sex, high birth weight, and white race. We have also provided data that supports an increased risk for AML following higher birth weights, and demonstrated an association with low Apgar scores.</p

MicroRNA-34a upregulation during seizure-induced neuronal death

MicroRNAs (miRNAs) are short, noncoding RNAs that function as posttranscriptional regulators of gene expression by controlling translation of mRNAs. A subset of miRNAs may be critical for the control of cell death, including the p53-regulated miRNA, miR-34a. Because seizures activate p53, and p53-deficient mice are reportedly resistant to damage caused by prolonged seizures, we investigated the role of miR-34a in seizure-induced neuronal death in vivo. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in mice. This led to an early (2 h) multifold upregulation of miR-34a in the CA3 and CA1 hippocampal subfields and lower protein levels of mitogen-activated kinase kinase kinase 9, a validated miR-34a target. Immunoprecipitation of the RNA-induced silencing complex component, Argonaute-2, eluted significantly higher levels of miR-34a after seizures. Injection of mice with pifithrin-α, a putative p53 inhibitor, prevented miR-34a upregulation after seizures. Intracerebroventricular injection of antagomirs targeting miR-34a reduced hippocampal miR-34a levels and had a small modulatory effect on apoptosis-associated signaling, but did not prevent hippocampal neuronal death in models of either severe or moderate severity status epilepticus. Thus, prolonged seizures cause subfield-specific, temporally restricted upregulation of miR-34a, which may be p53 dependent, but miR-34a is probably not important for seizure-induced neuronal death in this model

How to prevent ROP in preterm infants in Indonesia?

Background and Aims: Retinopathy of prematurity (ROP) is a severe disease in preterm infants. It is seen more frequently in Low-Middle Income Countries (LMIC) like Indonesia compared to High-Income Countries (HIC). Risk factors for ROP development are -extreme- preterm birth, use of oxygen, neonatal infections, respiratory problems, inadequate nutrition, and blood and exchange transfusions. In this paper, we give an overview of steps that can be taken in LMIC to prevent ROP and provide guidelines for screening and treating ROP. Methods: Based on the literature search and data obtained by us in Indonesia's studies, we propose guidelines for the prevention, screening, and treatment of ROP in preterm infants in LMIC. Results: Prevention of ROP starts before birth with preventing preterm labor, transferring a mother who might deliver <32 weeks to a perinatal center and giving corticosteroids to mothers that might deliver <34 weeks. Newborn resuscitation must be done using room air or, in the case of very preterm infants (<29-32 weeks) by using 30% oxygen. Respiratory problems must be prevented by starting continuous positive airway pressure (CPAP) in all preterm infants <32 weeks and in case of respiratory problems in more mature infants. If needed, the surfactant should be given in a minimally invasive manner, as ROP's lower incidence was found using this technique. The use of oxygen must be strictly regulated with a saturation monitor of 91-95%. Infections must be prevented as much as possible. Both oral and parenteral nutrition should be started in all preterm infants on day one of life with preferably mothers' milk. Blood transfusions can be prevented by reducing the amount of blood needed for laboratory analysis. Discussion: Preterm babies should be born in facilities able to care for them optimally. The use of oxygen must be strictly regulated. ROP screening is mandatory in infants born <34 weeks, and infants who received supplemental oxygen for a prolonged period. In case of progression of ROP, immediate mandatory treatment is required. Conclusion: Concerted action is needed to reduce the incidence of ROP in LMIC. "STOP - R1O2P3" is an acronym that can help implement standard practices in all neonatal intensive care units in LMIC to prevent development and progression

Ejection Time-Corrected Systolic Velocity Improves Accuracy in the Evaluation of Myocardial Dysfunction: A Study in Piglets

This study aimed to assess the effect of correcting for the impact of heart rate (HR) or ejection time (ET) on myocardial velocities in the long axis in piglets undergoing hypoxia. The ability to eject a higher volume at a fixed ET is a characteristic of contractility in the heart. Systolic velocity of the atrioventricular annulus displacement is directly related to volume changes of the ventricle. Both ET and systolic velocity may be measured in a single heartbeat. In 29 neonatal pigs, systolic velocity and ET were measured with tissue Doppler techniques in the mitral valve annulus, the tricuspid valve annulus, and the septum. All ejection time corrected velocities (S(ET), mean ± SEM, cm/s) decreased significantly during hypoxia (Smva(ET) 15.5 ± 0.2 to 13.2 ± 0.3 (p < 0.001), Sseptal(ET) 9.9 ± 0.1 to 7.8 ± 0.2 (p < 0.001), Stva(ET) 12.1 ± 0.2 to 9.8 ± 0.3 (p < 0.001)). The magnitude of change from baseline to hypoxia was greater for ejection time corrected systolic velocities than for RR-interval corrected velocities (mean ± SEM, cm/s); ΔSmva(ET) 2.3 ± 2.0 vs. ΔSmva(RR) 1.6 ± 1.1 (p = 0.02), ΔSseptal(ET) 2.1 ± 1.0 vs. ΔSseptal(RR) 1.6 ± 1.0 (p < 0.01), ΔStva(ET) 2.3 ± 1.1 vs. ΔStva(RR) 1.8 ± 1.3 (p = 0.04). The receiver operator characteristic (ROC) showed superior performance of S(ET) compared with uncorrected velocities. The decrease in S(ET) during hypoxia was not influenced by important hemodynamic determinants. ET-corrected systolic velocity improves accuracy and decreases variability in the evaluation of systolic longitudinal function and contractility during global hypoxia in neonatal pigs compared with systolic velocity alone. It is robust toward hemodynamic changes. This novel method has the potential of becoming a useful tool in clinical practice

A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes

The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types

Total antioxidant activity and trace elements in human milk: the first 4 months of breast-feeding

The content of many nutrients in breast milk are dependent on the nutritional status of the lactating woman. This is particularly true for fat and water-soluble vitamins, some of which have antioxidant properties. The aim of the study entertained herein was to evaluate the changes in total antioxidant status of human milk during the first 4 months of lactation, and to correlate such changes with the contents in specific antioxidant oligoelements (Cu, Zn, Mn and Se). Milk samples were collected from (31) lactating women recruited at the Service of Obstetrics of the Hospital de São João in Porto, after 1, 4, 8, 12 and 16 weeks after birth. The total antioxidant status (TAS) of human milk was measured by the Randox® commercial kit and trace metals by ICP-MS (inductively coupled plasma-mass spectrometry). The results found for TAS and oligoelements under study show a decrease in the concentration of these parameters from 7 days to 4 months of breast-feeding and significant correlations (p < 0.05) were found between TAS and Cu, Zn and Se (not Mn). The decreases of Cu, Zn and Se were also correlated, but not proportional between them, suggesting diverse excretion mechanisms for all. Between primipara and multipara women, a significant difference was found only for Cu and Zn concentrations at 7 days of lactation, but not for the other metals or TAS. With respect to the mother’s age, no correlation was found, either for trace metal concentrations or TAS

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches.

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly