Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

ObjectiveTo analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns.Study designThe original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment.ResultsTwo hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window.ConclusionDespite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives

Maternal Low-Protein Diet or Hypercholesterolemia Reduces Circulating Essential Amino Acids and Leads to Intrauterine Growth Restriction

OBJECTIVE—We have examined maternal mechanisms for adult-onset glucose intolerance, increased adiposity, and atherosclerosis using two mouse models for intrauterine growth restriction (IUGR): maternal protein restriction and hypercholesterolemia

Can we apply the Mendelian randomization methodology without considering epigenetic effects?

<p>Abstract</p> <p>Introduction</p> <p>Instrumental variable (IV) methods have been used in econometrics for several decades now, but have only recently been introduced into the epidemiologic research frameworks. Similarly, Mendelian randomization studies, which use the IV methodology for analysis and inference in epidemiology, were introduced into the epidemiologist's toolbox only in the last decade.</p> <p>Analysis</p> <p>Mendelian randomization studies using instrumental variables (IVs) have the potential to avoid some of the limitations of observational epidemiology (confounding, reverse causality, regression dilution bias) for making causal inferences. Certain limitations of randomized controlled trials, such as problems with generalizability, feasibility and ethics for some exposures, and high costs, also make the use of Mendelian randomization in observational studies attractive. Unlike conventional randomized controlled trials (RCTs), Mendelian randomization studies can be conducted in a representative sample without imposing any exclusion criteria or requiring volunteers to be amenable to random treatment allocation.</p> <p>Within the last decade, epigenetics has gained recognition as an independent field of study, and appears to be the new direction for future research into the genetics of complex diseases. Although previous articles have addressed some of the limitations of Mendelian randomization (such as the lack of suitable genetic variants, unreliable associations, population stratification, linkage disequilibrium (LD), pleiotropy, developmental canalization, the need for large sample sizes and some potential problems with binary outcomes), none has directly characterized the impact of epigenetics on Mendelian randomization. The possibility of epigenetic effects (non-Mendelian, heritable changes in gene expression not accompanied by alterations in DNA sequence) could alter the core instrumental variable assumptions of Mendelian randomization.</p> <p>This paper applies conceptual considerations, algebraic derivations and data simulations to question the appropriateness of Mendelian randomization methods when epigenetic modifications are present.</p> <p>Conclusion</p> <p>Given an inheritance of gene expression from parents, Mendelian randomization studies not only need to assume a random distribution of alleles in the offspring, but also a random distribution of epigenetic changes (e.g. gene expression) at conception, in order for the core assumptions of the Mendelian randomization methodology to remain valid. As an increasing number of epidemiologists employ Mendelian randomization methods in their research, caution is therefore needed in drawing conclusions from these studies if these assumptions are not met.</p

Complications Associated with Parenteral Nutrition in the Neonate

Although parenteral nutrition (PN) is life-sustaining, it is associated with many complications including parenteral nutrition-associated liver disease (PNALD) and central line-associated bloodstream infections (CLASBIs), which carry a high morbidity and mortality and impose a burden on the health care system. Evidence has emerged that the dose and composition of intravenous lipid products may alter the incidence of PNALD. However, other patient and PN-related factors, such as prematurity, birth weight, and gastrointestinal anatomy and function, are important. To improve neonatal care, future research on optimizing the content of PN and decreasing the incidence IFALD and CLASBIs is required

Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression

Early life nutritional intervention causes adult-onset insulin resistance and obesity in rats. Thyroid hormone receptor (TR), in turn, transcriptionally enhances skeletal muscle Glut4 expression. We tested the hypothesis that reduced circulating thyroid-stimulating hormone and T4 concentrations encountered in postnatal (PN4-PN24) high-carbohydrate (HC) milk formula-fed versus the mother-fed controls (MF) would epigenetically interfere with TR induction of adult (100 days) male rat skeletal muscle Glut4 expression, thereby providing a molecular mechanism mediating insulin resistance. We observed increased DNA methylation of the CpG island with enhanced recruitment of Dnmt3a, Dnmt3b and MeCP2 in the glut4 promoter region along with reduced acetylation of histone (H)2A.Z and H4 particularly at the H4.lysine (K)16 residue, which was predominantly mediated by histone deacetylase 4 (HDAC4). This was followed by enhanced recruitment of heterochromatin protein 1β to the glut4 promoter with increased Suv39H1 methylase concentrations. These changes reduced TR binding of the T3 response element of the glut4 gene (TREs; -473 to -450 bp) detected qualitatively in vivo (electromobility shift assay) and quantified ex vivo (chromatin immunoprecipitation). In addition, the recruitment of steroid receptor coactivator and CREB-binding protein to the glut4 promoter-protein complex was reduced. Co-immunoprecipitation experiments confirmed the interaction between TR and CBP to be reduced and HDAC4 to be enhanced in HC versus MF groups. These molecular changes were associated with diminished skeletal muscle Glut4 mRNA and protein concentrations. We conclude that early postnatal exposure to HC diet epigenetically reduced TR induction of adult male skeletal muscle Glut4 expression, uncovering novel molecular mechanisms contributing to adult insulin resistance and obesity

Adult glut3 homozygous null mice survive to demonstrate neural excitability and altered neurobehavioral responses reminiscent of neurodevelopmental disorders

Since GLUT3 is vital for fueling neurotransmission, we examined in-vivo the adult phenotype carrying the conditional homozygous glut3 gene mutation (KO) in glutamate-excitatory neurons. These KO mice demonstrated sex-specific differences in brain and body weights (p&nbsp;=&nbsp;0.0001 and p&nbsp;=&nbsp;0.01 each) with reduced GLUT3 protein in cerebral cortices and brain stem (p&nbsp;=&nbsp;0.005). In patch clamp studies the glut3 KO mice displayed a shorter latency to and enhanced paroxysmal activity (p&nbsp;=&nbsp;0.01 and p&nbsp;=&nbsp;0.015 each) in pyramidal neurons upon application of a GABAA antagonist, supporting hyperexcitability. Further, associated changes in neurobehavior consisted of reduced latency to fall in the rotorod motor test related to incoordination, increased distance traveled in total and periphery versus center in open field testing suggesting hyperactivity with anxiety (p&nbsp;=&nbsp;0.0013 in male, p&nbsp;=&nbsp;0.045 in female), reduced time freezing reminiscent of disrupted contextual fear conditioning (p&nbsp;=&nbsp;0.0033), decreased time in target quadrant seen with spatial cognitive memory water maze testing (p&nbsp;=&nbsp;0.034), and enhanced sociability particularly for novelty reflecting a lack of inhibition/impulsivity (p&nbsp;=&nbsp;0.038). Some of these features were equally pronounced in males and females (cognitive) while others were seen in females (anxiety and impulsivity). We conclude that GLUT3 in adult glutamate-excitatory neurons is essential for maintaining neurotransmitory equipoise regulating excitation with maintenance of motor coordination and activity, cognition, spatial memory and normal fear for both contextual events and novelty with tempered sociability. While sex-specificity was forthcoming for some of these behaviors, our findings collectively suggest that loss-of-function glut3 gene mutations or polymorphisms may underlie an endophenotype of attention deficit-hyperactivity disorder