Enrollment of Neonates in More Than One Clinical Trial

Because the highest rates of morbidity and mortality in neonates are seen in those born at 1 clinical trial. Neonatal units that have the infrastructure and resources to engage in research frequently face the question of whether it is permissible to enroll a neonate in >1 trial. This article examines the pertinent scientific, ethical, regulatory, and industry issues that should be taken into account when considering enrolling neonates in multiple clinical studies

Measurements of ψ(2S) and X(3872) → J/ψπ+π− production in pp collisions at √s=8 TeV with the ATLAS detector

Differential cross sections are presented for the prompt and non-prompt production of the hidden-charm states X(3872) and ψ(2S), in the decay mode J/ψπ+π−, measured using 11.4 fb−1 of pp collisions at √s=8 TeV by the ATLAS detector at the LHC. The ratio of cross-sections X(3872)/ψ(2S) is also given, separately for prompt and non-prompt components, as well as the non-prompt fractions of X(3872) and ψ(2S). Assuming independent single effective lifetimes for non-prompt X(3872) and ψ(2S) production gives RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2RB=B(B→X(3872)+any)B(X(3872)→J/ψπ+π−)B(B→ψ(2S)+any)B(ψ(2S)→J/ψπ+π−)=(3.95±0.32(stat)±0.08(sys))×10−2 separating short- and long-lived contributions, assuming that the short-lived component is due to Bc decays, gives RB = (3.57 ± 0.33(stat) ± 0.11(sys)) × 10−2, with the fraction of non-prompt X(3872) produced via Bc decays for pT(X(3872)) > 10 GeV being (25 ± 13(stat) ± 2(sys) ± 5(spin))%. The distributions of the dipion invariant mass in the X(3872) and ψ(2S) decays are also measured and compared to theoretical predictions

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Thyroxin and development of hepatic microsomal drug oxidation and electron transport in man and rats.

The neonatal phase of the ontogenetic pattern of hepatic microsomal mixed function oxidases (HMMFQ) in man and the influence of thyroid hormone on this ontogenetic pattern in rats were studied. In the neonatal period in man, there is a significant deficiency in the activity of hepatic microsomal aminopyrine N-demethylase, aniline p-hydroxylase, NADPH oxidase, NADPH cytochrome c reductase and in the amount of cytochrome P-450 and no measurable activity of NADPH cytochrome P-450 reductase. All of these enzymes except aminopyrine N-demethylase significantly correlated with postconceptional age indicating that significantly developmental events occur during the newborn period. [...]Nous avons étudie l'ontogénèse des oxidases hépatiques à function mixte chèz l'homme, et l'influence des hormones thyroidiennes sur l'ontogénèse de ces enzymes chez le rat. Durant la période néonatale chez l'homme, on observe une déficience significative de l'aminopyrine-N-danethylase, de l'aniline-p-hydroxylase, de l'NADPH oxidase, NADPH cytochrane c reductase et du cytochrome P-450, tandis que l'NADPH cytochrome P-450 reductase n'est pas mesurable

Chorioamnionitis and Ontogeny of Circulating Prostaglandin and Thromboxane in Preterm Infants

Our objective was to determine the effect of chorioamnionitis on plasma prostaglandin E2 (PGE2) and thromboxane 132 (TxB2) during the first week in preterm infants. Plasma PGE2 and TxB2 were measured at 1, 3, and 7 days of age in preterm infants (birth weights 501 to 1500 g), with (n = 26) and without (n = 22) chorioamnionitis. Infants with maternal chorioamnionitis had significantly lower mean gestational age (p = 0.0001) and birth weight (p = 0.03) and a marginally higher rate of bronchopulmonary dysplasia (37% versus 12.5, p = 0.05), a result that may be related to the lower mean gestational age. Plasma PGE2 and TxB2 varied widely, more so on the first day but did not significantly differ between the two groups. TxB2 was lower among infants who died or developed morbidities. Circulating PGE2 and TxB2 concentrations in preterm infants in the first week vary considerably, are relatively unaltered by chorioamnionitis, and are lower in association with mortality and clinical morbidities. Further research on their role in the causation of adverse neonatal outcomes is necessary

Dose Response of Bumetanide on Aquaporins and Angiogenesis Biomarkers in Human Retinal Endothelial Cells Exposed to Intermittent Hypoxia

Aquaporins (AQPs) are important for regulating cellular water, solute transport, and balance. Recently, AQPs have also been recognized as playing a key role in cell migration and angiogenesis. In the retina, hypoxia induces vascular endothelial growth factor (VEGF), a potent angiogenic and vascular permeability factor, resulting in retinal edema, which is facilitated by AQPs. Bumetanide is a diuretic agent and AQP 1–4 blocker. We tested the hypothesis that bumetanide suppression of AQPs ameliorates intermittent hypoxia (IH)-induced angiogenesis and oxidative stress in human microvascular retinal endothelial cells (HMRECs). HMRECs were treated with a low-dose (0.05 µg/mL) or high-dose (0.2 µg/mL) of bumetanide and were exposed to normoxia (Nx), hyperoxia (50% O2), or IH (50% O2 with brief hypoxia 5% O2) for 24, 48, and 72 h. Angiogenesis and oxidative stress biomarkers were determined in the culture media, and the cells were assessed for tube formation capacity and AQP-1 and -4 expression. Both doses of bumetanide significantly decreased oxidative stress and angiogenesis biomarkers. This response was reflected by reductions in tube formation capacity and AQP expression. These findings confirm the role of AQPs in retinal angiogenesis. Therapeutic targeting of AQPs with bumetanide may be advantageous for IH-induced aberrant retinal development

Combined antenatal and postnatal steroid effects on fetal and postnatal growth, and neurological outcomes in neonatal rats.

Preterm infants are often exposed to both antenatal and postnatal glucocorticoids (GCs). We tested the hypothesis that combined antenatal and postnatal GCs have long-lasting adverse effects on fetal and neonatal growth, growth factors, and neurological outcomes. Pregnant rats were administered a single IM dose of betamethasone (0.2 mg/Kg, AB), dexamethasone (0.2 mg/Kg, AD), or equivalent volumes of saline (AS) at 17 & 18 days gestation. Following delivery, pups from each treatment group were sacrificed at P0, and the remainder was treated with a single IM dose of either betamethasone (0.25 mg/Kg, PB), dexamethasone (0.25 mg/Kg, PD), or equivalent volumes of saline (PS) on P5, P6, and P7. Somatic growth, neurological status, and growth factors were determined at P14, P21, and P45. At birth, AD resulted in decreased somatic growth. AB advanced the hopping reflex associated with spinal rhythmic mechanisms. At P21, all GC groups were growth suppressed, but only the AS/PD group had deficits in brain weight and delayed plantar reflex associated with brainstem function. By P45, sustained reductions in body and brain weight occurred all combined antenatal and postnatal GC groups, as well as elevated ACTH and corticosterone. Retardation in plantar reflex occurred in all AD groups. IGF-I, GH and insulin levels were elevated at all ages with dexamethasone. Combined antenatal and postnatal GCs has persistent detrimental lasting effects on growth, growth factors, neurological outcomes, and HPA axis activity. Whether these effects persist in adult life and are risk factors for insulin resistance, remains to be elucidated

Pharmacodynamic Effects of Standard versus High Caffeine Doses in the Developing Brain of Neonatal Rats Exposed to Intermittent Hypoxia

(1) Background: Caffeine citrate, at standard doses, is effective for reducing the incidence of apnea of prematurity (AOP) and may confer neuroprotection and decrease neonatal morbidities in extremely low gestational age neonates (ELGANs) requiring oxygen therapy. We tested the hypothesis that high-dose caffeine (HiC) has no adverse effects on the neonatal brain. (2) Methods: Newborn rat pups were randomized to room air (RA), hyperoxia (Hx) or neonatal intermittent hypoxia (IH), from birth (P0) to P14 during which they received intraperitoneal injections of LoC (20 mg/kg on P0; 5 mg/kg/day on P1-P14), HiC (80 mg/kg; 20 mg/kg), or equivalent volume saline. Blood gases, histopathology, myelin and neuronal integrity, and adenosine receptor reactivity were assessed. (3) Results: Caffeine treatment in Hx influenced blood gases more than treatment in neonatal IH. Exposure to neonatal IH resulted in hemorrhage and higher brain width, particularly in layer 2 of the cerebral cortex. Both caffeine doses increased brain width in RA, but layer 2 was increased only with HiC. HiC decreased oxidative stress more effectively than LoC, and both doses reduced apoptosis biomarkers. In RA, both caffeine doses improved myelination, but the effect was abolished in Hx and neonatal IH. Similarly, both doses inhibited adenosine 1A receptor in all oxygen environments, but adenosine 2A receptor was inhibited only in RA and Hx. (4) Conclusions: Caffeine, even at high doses, when administered in normoxia, can confer neuroprotection, evidenced by reductions in oxidative stress, hypermyelination, and increased Golgi bodies. However, varying oxygen environments, such as Hx or neonatal IH, may alter and modify pharmacodynamic actions of caffeine and may even override the benefits caffeine