Short and random: Modelling the effects of (proto-)neural elongations

To understand how neurons and nervous systems first evolved, we need an account of the origins of neural elongations: Why did neural elongations (axons and dendrites) first originate, such that they could become the central component of both neurons and nervous systems? Two contrasting conceptual accounts provide different answers to this question. Braitenberg's vehicles provide the iconic illustration of the dominant input-output (IO) view. Here the basic role of neural elongations is to connect sensors to effectors, both situated at different positions within the body. For this function, neural elongations are thought of as comparatively long and specific connections, which require an articulated body involving substantial developmental processes to build. Internal coordination (IC) models stress a different function for early nervous systems. Here the coordination of activity across extended parts of a multicellular body is held central, in particular for the contractions of (muscle) tissue. An IC perspective allows the hypothesis that the earliest proto-neural elongations could have been functional even when they were initially simple short and random connections, as long as they enhanced the patterning of contractile activity across a multicellular surface. The present computational study provides a proof of concept that such short and random neural elongations can play this role. While an excitable epithelium can generate basic forms of patterning for small body-configurations, adding elongations allows such patterning to scale up to larger bodies. This result supports a new, more gradual evolutionary route towards the origins of the very first full neurons and nervous systems.Comment: 12 pages, 5 figures, Keywords: early nervous systems, neural elongations, nervous system evolution, computational modelling, internal coordinatio

Have we overlooked the role of mifepristone for the medical management of tubal ectopic pregnancy?

open access via the OUP Agreement Funding B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1176437).Peer reviewedPublisher PD

Socioeconomic Mediators of Racial and Ethnic Disparities in Congenital Heart Disease Outcomes: A Population-Based Study in California.

Background Racial/ethnic and socioeconomic disparities exist in outcomes for children with congenital heart disease. We sought to determine the influence of race/ethnicity and mediating socioeconomic factors on 1-year outcomes for live-born infants with hypoplastic left heart syndrome and dextro-Transposition of the great arteries. Methods and Results The authors performed a population-based cohort study using the California Office of Statewide Health Planning and Development database. Live-born infants without chromosomal anomalies were included. The outcome was a composite measure of mortality or unexpected hospital readmissions within the first year of life defined as >3 (hypoplastic left heart syndrome) or >1 readmissions (dextro-Transposition of the great arteries). Hispanic ethnicity was compared with non-Hispanic white ethnicity. Mediation analyses determined the percent contribution to outcome for each mediator on the pathway between race/ethnicity and outcome. A total of 1796 patients comprised the cohort (n=964 [hypoplastic left heart syndrome], n=832 [dextro-Transposition of the great arteries]) and 1315 were included in the analysis (n=477 non-Hispanic white, n=838 Hispanic). Hispanic ethnicity was associated with a poor outcome (crude odds ratio, 1.72; 95% confidence interval [CI], 1.37-2.17). Higher maternal education (crude odds ratio 0.5; 95% CI , 0.38-0.65) and private insurance (crude odds ratio, 0.65; 95% CI , 0.45-0.71) were protective. In the mediation analysis, maternal education and insurance status explained 33.2% (95% CI , 7-66.4) and 27.6% (95% CI , 6.5-63.1) of the relationship between race/ethnicity and poor outcome, while infant characteristics played a minimal role. Conclusions Socioeconomic factors explain a significant portion of the association between Hispanic ethnicity and poor outcome in neonates with critical congenital heart disease. These findings identify vulnerable populations that would benefit from resources to lessen health disparities

Initial Metabolic Profiles Are Associated with 7-Day Survival among Infants Born at 22-25 Weeks of Gestation.

OBJECTIVE:To evaluate the association between early metabolic profiles combined with infant characteristics and survival past 7 days of age in infants born at 22-25 weeks of gestation. STUDY DESIGN:This nested case-control consisted of 465 singleton live births in California from 2005 to 2011 at 22-25 weeks of gestation. All infants had newborn metabolic screening data available. Data included linked birth certificate and mother and infant hospital discharge records. Mortality was derived from linked death certificates and death discharge information. Each death within 7 days was matched to 4 surviving controls by gestational age and birth weight z score category, leaving 93 cases and 372 controls. The association between explanatory variables and 7-day survival was modeled via stepwise logistic regression. Infant characteristics, 42 metabolites, and 12 metabolite ratios were considered for model inclusion. Model performance was assessed via area under the curve. RESULTS:The final model included 1 characteristic and 11 metabolites. The model demonstrated a strong association between metabolic patterns and infant survival (area under the curve [AUC] 0.885, 95% CI 0.851-0.920). Furthermore, a model with just the selected metabolites performed better (AUC 0.879, 95% CI 0.841-0.916) than a model with multiple clinical characteristics (AUC 0.685, 95% CI 0.627-0.742). CONCLUSIONS:Use of metabolomics significantly strengthens the association with 7-day survival in infants born extremely premature. Physicians may be able to use metabolic profiles at birth to refine mortality risks and inform postnatal counseling for infants born at <26 weeks of gestation

Modeling spontaneous activity across an excitable epithelium: Support for a coordination scenario of early neural evolution

Internal coordination models hold that early nervous systems evolved in the first place to coordinate internal activity at a multicellular level, most notably the use of multicellular contractility as an effector for motility. A recent example of such a model, the skin brain thesis, suggests that excitable epithelia using chemical signaling are a potential candidate as a nervous system precursor.We developed a computational model and a measure for whole body coordination to investigate the coordinative properties of such excitable epithelia. Using this measure we show that excitable epithelia can spontaneously exhibit body-scale patterns of activation. Relevant factors determining the extent of patterning are the noise level for exocytosis, relative body dimensions, and body size. In smaller bodies whole-body coordination emerges from cellular excitability and bidirectional excitatory transmission alone.Our results show that basic internal coordination as proposed by the skin brain thesis could have arisen in this potential nervous system precursor, supporting that this configuration may have played a role as a proto-neural system and requires further investigation

Vascular and Neural Dysfunctions in Obese Zucker Rats: Effect of AVE7688

The purpose of this study was to determine whether AVE7688 a drug that inhibits both angiotensin converting enzyme and neutral endopeptidase activity protects vascular and nerve functions in an animal model of metabolic syndrome. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with AVE7688. Vasodilation in epineurial arterioles was measured by videomicroscopy and nerve conduction velocity was measured following electrical stimulation. Treatment with AVE7688 improved vascular relaxation in response to acetylcholine and motor and sensory nerve conduction velocity. In obese Zucker rats superoxide levels and nitrotyrosine staining were elevated in the aorta and treatment corrected both conditions. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and demonstrated signs of impaired tactile response and both conditions were significantly improved with treatment. Even though obese Zucker rats are normoglycemic vascular and neural dysfunctions develop with age and can be improved by treatment with AVE7688

The Gross--Llewellyn Smith Sum Rule in the Analytic Approach to Perturbative QCD

We apply analytic perturbation theory to the Gross--Llewellyn Smith sum rule. We study the $Q^2$ evolution and the renormalization scheme dependence of the analytic three-loop QCD correction to this sum rule, and demonstrate that the results are practically renormalization scheme independent and lead to rather different $Q^2$ evolution than the standard perturbative correction possesses.Comment: 17 pages, 9 eps figures, REVTe

Second trimester inflammatory and metabolic markers in women delivering preterm with and without preeclampsia.

ObjectiveInflammatory and metabolic pathways are implicated in preterm birth and preeclampsia. However, studies rarely compare second trimester inflammatory and metabolic markers between women who deliver preterm with and without preeclampsia.Study designA sample of 129 women (43 with preeclampsia) with preterm delivery was obtained from an existing population-based birth cohort. Banked second trimester serum samples were assayed for 267 inflammatory and metabolic markers. Backwards-stepwise logistic regression models were used to calculate odds ratios.ResultsHigher 5-α-pregnan-3β,20α-diol disulfate, and lower 1-linoleoylglycerophosphoethanolamine and octadecanedioate, predicted increased odds of preeclampsia.ConclusionsAmong women with preterm births, those who developed preeclampsia differed with respect metabolic markers. These findings point to potential etiologic underpinnings for preeclampsia as a precursor to preterm birth

Evaluation of the zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles

Representative animal models for diabetes-associated vascular complications are extremely relevant in assessing potential therapeutic drugs. While several rodent models for type 2 diabetes (T2D) are available, their relevance in recapitulating renal and cardiovascular features of diabetes in man is not entirely clear. Here we evaluate at the molecular level the similarity between Zucker diabetic fatty (ZDF) rats, as a model of T2D-associated vascular complications, and human disease by urinary proteome analysis. Urine analysis of ZDF rats at early and late stages of disease compared to age- matched LEAN rats identified 180 peptides as potentially associated with diabetes complications. Overlaps with human chronic kidney disease (CKD) and cardiovascular disease (CVD) biomarkers were observed, corresponding to proteins marking kidney damage (eg albumin, alpha-1 antitrypsin) or related to disease development (collagen). Concordance in regulation of these peptides in rats versus humans was more pronounced in the CVD compared to the CKD panels. In addition, disease-associated predicted protease activities in ZDF rats showed higher similarities to the predicted activities in human CVD. Based on urinary peptidomic analysis, the ZDF rat model displays similarity to human CVD but might not be the most appropriate model to display human CKD on a molecular level