Pericytes promote selective vessel regression to regulate vascular patterning

Blood vessel networks form in a 2-step process of sprouting angiogenesis followed by selective branch regression and stabilization of remaining vessels. Pericytes are known to function in stabilizing blood vessels, but their role in vascular sprouting and selective vessel regression is poorly understood. The endosialin (CD248) receptor is expressed by pericytes associated with newly forming but not stable quiescent vessels. In the present study, we used the Endosialin(-/-) mouse as a means to uncover novel roles for pericytes during the process of vascular network formation. We demonstrate in a postnatal retina model that Endosialin(-/-) mice have normal vascular sprouting but are defective in selective vessel regression, leading to increased vessel density. Examination of the Endosialin(-/-) mouse tumor vasculature revealed an equivalent phenotype, indicating that pericytes perform a hitherto unidentified function to promote vessel destabilization and regression in vivo in both physiologic and pathologic angiogenesis. Mechanistically, Endosialin(-/-) mice have no defect in pericyte recruitment. Rather, endosialin binding to an endothelial associated, but not a pericyte associated, basement membrane component induces endothelial cell apoptosis and detachment. The results of the present study advance our understanding of pericyte biology and pericyte/endothelial cell cooperation during vascular patterning and have implications for the design of both pro- and antiangiogenic therapies.     

Impact of Highly Active Antiretroviral Therapy on paediatric Human Immunodeficiency Virus-associated left ventricular dysfunction within the Johannesburg teaching hospital complex

OBJECTIVE: To analyse the outcome of children with left ventricular dysfunction placed on Highly Active Antiretroviral Therapy. Method This study is a retrospective review of records of Human Immunodeficiency Virus-positive children with left ventricular dysfunction. Demographic data were collected. Left ventricular fractional shortening, CD4 percentage, viral load, and nutritional status were compared before and during antiretroviral therapy. RESULTS: We reviewed the records of 34 Human Immunodeficiency Virus-positive children with left ventricular dysfunction. In all, 18 patients received antiretroviral therapy (group one) and 16 were antiretroviral therapy naive (group two). The median age of group one at initial visit was 94 months, with a male-to-female ratio of 1:1. Of those, 17 children showed improved left ventricular function on treatment, with an increase in fractional shortening (median: 17-33.5%; p less than 0.0001). There was no significant statistical difference between the groups regarding initial fractional shortening. In group one, the CD4 percentage improved (median: 12% to 30.5%; p less than 0.0001), with viral load suppression (median: 24,900 copies per millilitre to less than 25 copies per millilitre; p less than 0.0001). There was weight gain in group one (median z-score: -1.70 to -1.32; p equal to 0.0083). Proper statistical analysis in group two was not possible because of poor follow-up of patients. Conclusion The findings are in keeping with other reports that have shown improvement in left ventricular function in patients with Human Immunodeficiency Virus-associated cardiomyopathy treated with Highly Active Antiretroviral Therapy. Recovery of myocardial function is associated with improvement in immunological and nutritional statuses.     

Cost-effectiveness of primary prevention of paediatric asthma: a decision-analytic model

Background

Many children stand to benefit from being asthma-free for life with primary (i.e., prenatally started) prevention addressing one environmental exposure in a unifaceted (UF) approach or at least two in a multifaceted (MF) approach. We assessed the cost-effectiveness of primary prevention programmes for Dutch children in a decision-analytic framework.

Methods

A decision-analytic tree model analysing healthcare costs and asthma cases prevented was developed to compare usual care (UC) with two UF and three MF programmes on the primary prevention of asthma amongst children. Programmes were evaluated through incremental cost-effectiveness ratios and net monetary benefits. Decision and parameter uncertainty were subjected to value-of-information analyses.

Results

The current UC and one of three MF programmes dominated the other alternatives. The MF programme was more costly but also more effective than UC at an incremental cost-effectiveness ratio of €8,209.20/additional asthma case prevented. The value of perfect information to reduce uncertainty was €291.6M at its lowest. Most of the uncertainty in the cost-effectiveness threshold was attributable to the probability and cost estimates for low-risk children.

Conclusion

This study supports the feasibility of a structured programme that simultaneously addresses exposure to house dust mites, pet dander, environmental tobacco, and breast-feeding as a cost-effective alternative to UC in the primary prevention of asthma amongst children.     

The miR-200c/141-ZEB2-TGFb axis is aberrant in human T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL consists of phenotypic and/or genotypic subgroups that may explain the heterogeneity of the disease. Multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups, and no clear T-cell receptor a or b CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of microRNA (miRNA) is aberrant and often heterogeneous in T-PLL. We identified 35 miRNA that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR- 200c/141 and miR-181a/181b expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 correlated with downregulation of their targets ZEB2 and TGFbR3 and aberrant TGFb1- induced phosphorylated SMAD2 (p-SMAD2) and p-SMAD3, indicating that the TGFb pathway is affected in T-PLL. Our results thus highlight the potential role for aberrantly expressed oncogenic miRNA in T-PLL and pave the way for new therapeutic targets in this disease.     

An Infant Formula with Large,Milk Phospholipid-Coated Lipid Droplets Supports Adequate Growth and Is Well-Tolerated in Healthy,Term Asian Infants: A Randomized,Controlled Double-Blind Clinical Trial

Lipids are essential for healthy infant growth and development. The structural complexity of lipids in human milk is not present in infant milk formula (IF). A concept IF was developed mimicking more closely the structure and composition of human milk fat globules. The current study evaluates whether a concept IF with large, milk phospholipid-coated lipid droplets (mode diameter 3 to 5 μm) is equivalent to standard IF with regard to growth adequacy and safety in healthy, term Asian infants. In this randomized, double-blind, controlled trial, infants were randomized after parents decided to introduce formula. Infants received a standard IF with (Control) or without the specific prebiotic mixture scGOS/lcFOS (9:1 ratio; Control w/o prebiotics), or a Concept IF with large, milk phospholipid-coated lipid droplets and the prebiotic mixture. A group of 67 breastfed infants served as a reference. As a priori defined, only those infants who were fully intervention formula-fed ≤28 days of age were included in the equivalence analysis (Control n = 29; Control w/o prebiotics n = 28; Concept n = 35, per-protocol population). Primary outcome was daily weight gain during the first four months of life, with the difference between the Concept and Control as the key comparison of interest. Additionally, adverse events, growth and tolerance parameters were evaluated. Equivalence of daily weight gain was demonstrated between the Concept and Control group after additional correction for ethnicity and birthweight (difference in estimated means of 0.1 g/d, 90%CI [−2.30, 2.47]; equivalence margin +/− 3 g/d). No clinically relevant group differences were observed in secondary growth outcomes, tolerance outcomes or number, severity or relatedness of adverse events. This study corroborates that an infant formula with large, milk phospholipid-coated lipid droplets supports adequate growth and is well tolerated and safe for use in healthy infants.