Cold-inducible RNA-binding protein (CIRP) and RNA-binding motif protein 3 (RBM3) are two evolutionarily conserved RNA-binding proteins that are transcriptionally upregulated in response to low ...temperature. Featuring an RNA-recognition motif (RRM) and an arginine–glycine-rich (RGG) domain, these proteins display many similarities and specific disparities in the regulation of numerous molecular and cellular events. The resistance to serum withdrawal, endoplasmic reticulum stress, or other harsh conditions conferred by RBM3 has led to its reputation as a survival gene. Once CIRP protein is released from cells, it appears to bolster inflammation, contributing to poor prognosis in septic patients. A variety of human tumor specimens have been analyzed for CIRP and RBM3 expression. Surprisingly, RBM3 expression was primarily found to be positively associated with the survival of chemotherapy-treated patients, while CIRP expression was inversely linked to patient survival. In this comprehensive review, we summarize the evolutionary conservation of CIRP and RBM3 across species as well as their molecular interactions, cellular functions, and roles in diverse physiological and pathological processes, including circadian rhythm, inflammation, neural plasticity, stem cell properties, and cancer development.
Mechanical ventilation via an endotracheal tube is a risk factor for bronchopulmonary dysplasia (BPD), one of the most common morbidities of very preterm infants. Our objective was to investigate the ...effect that strategies to avoid endotracheal mechanical ventilation (eMV) have on the incidence of BPD in preterm infants <30 weeks' gestational age (GA).
In February 2013, we searched the databases Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study selection criteria included randomized controlled trials published in peer-reviewed journals since the year 2000 that compared preterm infants <30 weeks' GA treated by using a strategy aimed at avoiding eMV with a control group in which mechanical ventilation via an endotracheal tube was performed at an earlier stage. Data were extracted and analyzed by using the standard methods of the Cochrane Neonatal Review Group. The authors independently assessed study eligibility and risk of bias, extracted data and calculated odds ratios and 95% confidence intervals, employing RevMan version 5.1.6.
We identified 7 trials that included a total of 3289 infants. The combined odds ratio (95% confidence interval) of death or BPD was 0.83 (0.71-0.96). The number needed to treat was 35. The study results were remarkably homogeneous. Avoiding eMV had no influence on the incidence of severe intraventricular hemorrhage.
Strategies aimed at avoiding eMV in infants <30 weeks' GA have a small but significant beneficial impact on preventing BPD.
Newborn infants face a rapid surge of oxygen and a more protracted rise of unconjugated bilirubin after birth. Bilirubin has a strong antioxidant capacity by scavenging free radicals, but it also ...exerts direct toxicity. This study investigates whether cultured rat alveolar epithelial cells type II (AEC II) react differently to bilirubin under different oxygen concentrations. The toxic threshold concentration of bilirubin was narrowed down by means of a cell viability test. Subsequent analyses of bilirubin effects under 5% oxygen and 80% oxygen compared to 21% oxygen, as well as pretreatment with bilirubin after 4 h and 24 h of incubation, were performed to determine the induction of apoptosis and the gene expression of associated transcripts of cell death, proliferation, and redox-sensitive transcription factors. Oxidative stress led to an increased rate of cell death and induced transcripts of redox-sensitive signaling pathways. At a non-cytotoxic concentration of 400 nm, bilirubin attenuated oxidative stress-induced responses and possibly mediated cellular antioxidant defense by influencing Nrf2/Hif1α- and NFκB-mediated signaling pathways. In conclusion, the study demonstrates that rat AEC II cells are protected from oxidative stress-induced impairment by low-dose bilirubin.
Observational studies demonstrating reduced rates of infections, necrotizing enterocolitis (NEC), and mortality in preterm infants fed their own mother's milk, as opposed to formula, have prompted ...endeavors to achieve similar effects with the right choice of food and food additives. In a systematic review of meta-analyses and randomized controlled trials (RCTs), we considered nutritional interventions aimed at reducing the rates of infections, NEC, or mortality in very preterm infants. The overall effects of particular interventions were presented as risk ratios with 95% confidence intervals. In RCTs, pasteurized human donor milk, as opposed to formula, reduced NEC but not infections or mortality. No differences emerged between infants receiving human or bovine milk-based fortifiers. Pooled data of small trials and a recent large RCT suggested that bovine lactoferrin reduced rates of fungal sepsis without impact on other infections, NEC, or mortality. Pooled data of RCTs assessing the use of prebiotic oligosaccharides found reduced infection but not mortality. Enteral L-glutamine (six RCTs) lowered infection rates, and enteral L-arginine (three RCTs) reduced NEC. A meta-analysis sensitivity approach found multiple-strain (but not single-strain) probiotics to be highly effective in reducing NEC and mortality. Thus, selected food components may help to improve outcomes in preterm infants.
Recombinant human erythropoietin (rhEPO) is a promising pharmacological agent for neuroprotection in neonates.
To investigate whether prophylactic rhEPO administration in very preterm infants ...improves neurodevelopmental outcomes in a meta-analysis of randomized controlled trials (RCTs).
Medline, Embase, and the Cochrane Central Register of Controlled Trials were searched in December 2016 and complemented by other sources.
RCTs investigating the use of rhEPO in preterm infants versus a control group were selected if they were published in a peer-reviewed journal and reported neurodevelopmental outcomes at 18 to 24 months' corrected age.
Data extraction and analysis followed the standard methods of the Cochrane Neonatal Review Group. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Secondary outcomes included a Psychomotor Development Index <70, cerebral palsy, visual impairment, and hearing impairment.
Four RCTs, comprising 1133 infants, were included in the meta-analysis. Prophylactic rhEPO administration reduced the incidence of children with an MDI <70, with an odds ratio (95% confidence interval) of 0.51 (0.31-0.81),
< .005. The number needed to treat was 14. There was no statistically significant effect on any secondary outcome.
Prophylactic rhEPO improved the cognitive development of very preterm infants, as assessed by the MDI at a corrected age of 18 to 24 months, without affecting other neurodevelopmental outcomes. Current and future RCTs should investigate optimal dosing and timing of prophylactic rhEPO and plan for long-term neurodevelopmental follow-up.
Paracetamol is commonly used to treat fever and pain in pregnant women, but there are growing concerns that this may cause attention deficit hyperactivity disorder and autism spectrum disorder in the ...offspring. A growing number of epidemiological studies suggests that relative risks for these disorders increase by an average of about 25% following intrauterine paracetamol exposure. The data analyzed point to a dose-effect relationship but cannot fully account for unmeasured confounders, notably indication and genetic transmission. Only few experimental investigations have addressed this issue. Altered behavior has been demonstrated in offspring of paracetamol-gavaged pregnant rats, and paracetamol given at or prior to day 10 of life to newborn mice resulted in altered locomotor activity in response to a novel home environment in adulthood and blunted the analgesic effect of paracetamol given to adult animals. The molecular mechanisms that might mediate these effects are unknown. Paracetamol has diverse pharmacologic actions. It reduces prostaglandin formation via competitive inhibition of the peroxidase moiety of prostaglandin H2 synthase, while its metabolite
-arachidonoyl-phenolamine activates transient vanilloid-subtype 1 receptors and interferes with cannabinoid receptor signaling. The metabolite
-acetyl-p-benzo-quinone-imine, which is pivotal for liver damage after overdosing, exerts oxidative stress and depletes glutathione in the brain already at dosages below the hepatic toxicity threshold. Given the widespread use of paracetamol during pregnancy and the lack of safe alternatives, its impact on the developing brain deserves further investigation.
While additional oxygen supply is often required for the survival of very premature infants in intensive care, this also brings an increasing risk of progressive lung diseases and poor long-term lung ...outcomes. Caffeine is administered to neonates in neonatal intensive care for the prevention and treatment of apneas and has been shown to reduce BPD incidence and the need for mechanical ventilation, although it is still unclear whether this is due to a direct pulmonary action via antagonism of adenosine receptors and/or an indirect action. This experimental study aims to investigate the action of caffeine on the oxidative stress response in pulmonary tissue in a hyperoxia-based model of bronchopulmonary dysplasia in newborn rats.
Newborn Wistar rats were exposed to 21% or 80% oxygen for 3 (P3) or 5 (P5) postnatal days with or without recovery on room air until postnatal day 15 (P15) and treated with vehicle or caffeine (10 mg/kg) every 48 h beginning on the day of birth. The lung tissue of the rat pups was examined for oxidative stress response at P3 and P5 immediately after oxygen exposure or after recovery in ambient air (P15) by immunohistological staining and analysis of lung homogenates by ELISA and qPCR.
Lungs of newborn rats, corresponding to the saccular stage of lung development and to the human lung developmental stage of preterms, showed increased rates of total glutathione and hydrogen peroxide, oxidative damage to DNA and lipids, and induction of second-phase mediators of antioxidative stress response (superoxide dismutase, heme oxygenase-1, and the Nrf2/Keap1 system) in response to hyperoxia. Caffeine reduced oxidative DNA damage and had a protective interference with the oxidative stress response.
In addition to the pharmacological antagonism of adenosine receptors, caffeine appears to be a potent antioxidant and modulates the hyperoxia-induced pulmonary oxidative stress response and thus protective properties in the BPD-associated animal model. Free-radical-induced damage caused by oxidative stress seems to be a biological mechanism progress of newborn diseases. New aspects of antioxidative therapeutic strategies to passivate oxidative stress-related injury should be in focus of further investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In orally fed preterm infants, poor weight gain may be linked to low fecal pancreatic elastase-1 (FPE-1) activity, indicative of exocrine pancreatic insufficiency. The objective of this study was the ...retrospective assessment of the effect of exogenous digestive enzyme replacement by gavage in preterm infants with growth failure and low FPE-1 (<200 μg/g). We analyzed weight gain relative to baseline and caloric intake during 14-day periods before and after institution of digestive enzyme replacement containing 6000 U lipase and 240 U protease kg
−1
d
−1
. Among 46 of 132 preterm infants < 1250g birth weight surviving to at least 14 days in whom FPE-1 was determined, 38 infants had low FPE-1 (< 200 μg/g), and 33 infants received exogenous digestive enzyme replacement. Average daily weight gain significantly increased from 14.4 range 2.6–22.4 g kg
−1
d
−1
to 17.4 8.4–29.0 g kg
−1
d
−1
(
P
= 0.001), as did weight gain per kcal, from 0.08 0.02–0.13 g kcal
−1
d
−1
to 0.11 0.05–0.18 g kcal
−1
d
−1
.
Conclusion
: In preterm infants with signs and symptoms of exocrine pancreatic insufficiency, exogenous digestive enzyme replacement is associated with improved growth.
What is Known:
• Very preterm infants on full enteral nutrition may display growth failure linked to transient poor exocrine pancreatic function.
• Porcine pancreatic enzymes covered with an acid-resistant coating are too large to pass the internal diameter of most gavage tubes used in very preterm infants.
What is New:
• Administration of a liquid formulation of acid-resistant microbial digestive enzymes in preterm infants with growth failure and low fecal pancreatic elastase-1 values was associated with improved weight gain.
• Response to exogenous digestive enzyme replacement was associated with the prior extent of growth failure.
The risk of oxidative stress is unavoidable in preterm infants and increases the risk of neonatal morbidities. Premature infants often require sedation and analgesia, and the commonly used opioids ...and benzodiazepines are associated with adverse effects. Impairment of cerebellar functions during cognitive development could be a crucial factor in neurodevelopmental disorders of prematurity. Recent studies have focused on dexmedetomidine (DEX), which has been associated with potential neuroprotective properties and is used as an off-label application in neonatal units. Wistar rats (P6) were exposed to 80% hyperoxia for 24 h and received as pretreatment a single dose of DEX (5µg/kg, i.p.). Analyses in the immature rat cerebellum immediately after hyperoxia (P7) and after recovery to room air (P9, P11, and P14) included examinations for cell death and inflammatory and oxidative responses. Acute exposure to high oxygen concentrations caused a significant oxidative stress response, with a return to normal levels by P14. A marked reduction of hyperoxia-mediated damage was demonstrated after DEX pretreatment. DEX produced a much earlier recovery than in controls, confirming a neuroprotective effect of DEX on alterations elicited by oxygen stress on the developing cerebellum.
Aim
The aim of this study was to assess the diagnostic approach to microcephaly in childhood and to identify the prevalence of the various underlying causes/disease entities.
Method
We conducted a ...retrospective study on a cohort of 680 children with microcephaly (399 males, 281 females; mean age at presentation 7–8mo, range 1mo–5y) from patients presenting to Charité – University Medicine Berlin (n=474) and University Hospital Dresden (n=206). Patient discharge letters were searched electronically to identify cases of microcephaly, and then the medical records of these patients were used to analyze parameters for distribution.
Results
The putative aetiology for microcephaly was ascertained in 59% of all patients, leaving 41% without a definite diagnosis. In the cohort of pathogenetically defined microcephaly, genetic causes were identified in about half of the patients, perinatal brain damage accounted for 45%, and postnatal brain damage for 3% of the cases. Microcephaly was associated with intellectual impairment in 65% of participants, epilepsy was diagnosed in 43%, and ophthalmological disorders were found in 30%. Brain magnetic resonance imaging revealed abnormalities in 76% of participants.
Interpretation
Microcephaly remains a poorly defined condition, and a uniform diagnostic approach is urgently needed. A definite aetiological diagnosis is important in order to predict the prognosis and offer genetic counselling. Identifying gene mutations as causes of microcephaly increases our knowledge of brain development and the clinical spectrum of microcephaly. We therefore propose a standardized initial diagnostic approach to microcephaly.
What this paper adds
The distribution of various aetiologies of microcephaly in the largest cohort of children to be studied to date.
The rate of success in diagnosing microcephaly is illustrated.
A uniform data documentation and standardized initial diagnostic approach to children with microcephaly is proposed.
This article is commented on by Holden on page 705 of this issue.
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