Epigenetic modifications may play a role in the developmental consequences of early life events

Many aspects of postnatal development are influenced by events before birth, including cognitive and language development. An adverse intrauterine environment, for example secondary to poor maternal nutritional status, multiple pregnancy, or late preterm birth, is associated with increased risks of delayed or impaired childhood development and altered physiology in adulthood that may predispose to increased risk of adult disease. Maternal periconceptional undernutrition and twin conception can both result in late preterm birth, but it is less clear whether cases of late preterm birth not following a recognized early pregnancy event may still have their origin in the periconceptional period. Thus, the very earliest periods of pregnancy, and perhaps even the pre-pregnancy period, may be an important period determining the developmental trajectory of the fetus, and thus both pregnancy and later health outcomes. Profound epigenetic modifications to the genome occur in the early embryo as a normal part of development. Recent evidence suggests that environmental signals acting during early development may also result in epigenetic changes which may play a role in mediating the association between early life exposures and later phenotype

Periconceptional Undernutrition in Sheep Affects Adult Phenotype Only in Males

Periconceptional undernutrition (PCUN) in sheep alters fetal growth and metabolism and postnatal growth regulation, but effects on adult body composition are unknown. We investigated the effects of PCUN on adult phenotype. Singleton lambs of ewes fed normally (N, n=17) or undernourished before (UN-61-0 d, n=23), before and after (UN-61-30 d, n=19), or after (UN-2-30d, n=17) mating (d0) were weighed at birth, 12 weeks, and intermittently to adulthood. At the age of 3-4 years, body composition was assessed by dual-emission X-ray absorptiometry followed by postmortem examination. Compared with N animals, male, but not female, offspring of all UN groups had greater % fat mass (all UN versus N: 9±1 versus 2±1%, P<0.001) and perirenal fat (544±36 versus 222±44 g, P=0.002), and proportionately smaller hearts (4.5±0.1 versus 5.2±0.2 g·kg−1), lungs (9.1±0.2 versus 10.6±0.5 g·kg−1), and adrenals (0.06±0.002 versus 0.08±0.003 g·kg−1). UN males also had larger testes (726±21 versus 545±32 g, P=0.007), but UN females had smaller ovaries (2.7±0.08 versus 3.4±0.4 g, P=0.01). Changes were independent of birth weight or postnatal growth velocity. Brief PCUN has sex-specific effects on adult phenotype, predominantly affecting males, which may contribute to adverse metabolic outcomes

Associations between neonatal nutrition and visual outcomes in 7-year-old children born very preterm

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm.METHODS: The study cohort comprised children (n = 128) with birthweight &lt;1500 g or gestational age &lt; 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years' corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models.RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02).CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.</p

Whole animal experiments should be more like human randomized controlled trials

Beverly S. Muhlhausler, Frank H. Bloomfield, Matthew W. Gillma

Weekly Intra-Amniotic IGF-1 Treatment Increases Growth of Growth-Restricted Ovine Fetuses and Up-Regulates Placental Amino Acid Transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway

COHESION: a core outcome set for the treatment of neonatal encephalopathy

BACKGROUND: Heterogeneity in outcomes reported in trials of interventions for the treatment of neonatal encephalopathy (NE) makes evaluating the effectiveness of treatments difficult. Developing a core outcome set for NE treatment would enable researchers to measure and report the same outcomes in future trials. This would minimise waste, ensure relevant outcomes are measured and enable evidence synthesis. Therefore, we aimed to develop a core outcome set for treating NE.METHODS: Outcomes identified from a systematic review of the literature and interviews with parents were prioritised by stakeholders (n = 99 parents/caregivers, n = 101 healthcare providers, and n = 22 researchers/ academics) in online Delphi surveys. Agreement on the outcomes was achieved at online consensus meetings attended by n = 10 parents, n = 18 healthcare providers, and n = 13 researchers/ academics.RESULTS: Seven outcomes were included in the final core outcome set: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child, and adverse events related to treatment.CONCLUSION: We developed a core outcome set for the treatment of NE. This will allow future trials to measure and report the same outcomes and ensure results can be compared. Future work should identify how best to measure the COS

A Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints: the COSGROVE study.

BACKGROUND: Fetal growth restriction refers to a fetus that does not reach its genetically predetermined growth potential. It is well-recognized that growth-restricted fetuses are at increased risk of both short- and long-term adverse outcomes. Systematic evaluation of the evidence from clinical trials of fetal growth restriction is often difficult because of variation in the outcomes that are measured and reported. The development of core outcome sets for fetal growth restriction studies would enable future trials to measure similar meaningful outcomes. OBJECTIVE: The purpose of this study was to develop core outcome sets for trials of prevention or treatment of fetal growth restriction. STUDY DESIGN: This was a Delphi consensus study. A comprehensive literature review was conducted to identify outcomes that were reported in studies of prevention or treatment of fetal growth restriction. All outcomes were presented for prioritization to key stakeholders (135 healthcare providers, 68 researchers/academics, and 35 members of the public) in 3 rounds of online Delphi surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core outcome set at a face-to-face meeting with 5 healthcare providers, 5 researchers/academics, and 6 maternity service users. RESULTS: In total, 22 outcomes were included in the final core outcome set. These outcomes were grouped under 4 domains: maternal (n=4), fetal (n=1), neonatal (n=12), and childhood (n=5). CONCLUSION: The Core Outcome Set for the prevention and treatment of fetal GROwth restriction: deVeloping Endpoints study identified a large number of potentially relevant outcomes and then reached consensus on those factors that, as a minimum, should be measured and reported in all future trials of prevention or treatment of fetal growth restriction. This will enable future trials to measure similar meaningful outcomes and to ensure that findings from different studies can be compared and combined

Imaging cortical activity following affective stimulation with a high temporal and spatial resolution

Keil J, Adenauer H, Catani C, Neuner F. Imaging cortical activity following affective stimulation with a high temporal and spatial resolution. BMC Neuroscience. 2009;10(1):83.Background:The affective and motivational relevance of a stimulus has a distinct impact on cortical processing, particularly in sensory areas. However, the spatial and temporal dynamics of this affective modulation of brain activities remains unclear. The purpose of the present study was the development of a paradigm to investigate the affective modulation of cortical networks with a high temporal and spatial resolution. We assessed cortical activity with MEG using a visual steady-state paradigm with affective pictures. A combination of a complex demodulation procedure with a minimum norm estimation was applied to assess the temporal variation of the topography of cortical activity. Results: Statistical permutation analyses of the results of the complex demodulation procedure revealed increased steady-state visual evoked field amplitudes over occipital areas following presentation of affective pictures compared to neutral pictures. This differentiation shifted in the time course from occipital regions to parietal and temporal regions. Conclusion: It can be shown that stimulation with affective pictures leads to an enhanced activity in occipital region as compared to neutral pictures. However, the focus of differentiation is not stable over time but shifts into temporal and parietal regions within four seconds of stimulation. Thus, it can be crucial to carefully choose regions of interests and time intervals when analyzing the affective modulation of cortical activity