Pulmonary prostacyclin is associated with less severe respiratory distress in preterm infants

BACKGROUND: Prostacyclin (PGI(2)) and thromboxane A(2) (TxA(2)) may take part in lung pathology; high concentrations of PGI(2) may protect newborn rabbits against hyperoxic lung injury, and TxA(2) may participate in the development of bronchopulmonary dysplasia (BPD). Aims: To examine in small preterm infants, the relationship between pulmonary PGI(2) and TxA(2) and respiratory distress during the early postnatal period. METHODS: The stable metabolite of prostacyclin, 6-keto-prostaglandinF(1 alpha), and that of thromboxane A(2), thromboxane B(2), were quantified by radioimmunoassays in 284 samples of tracheal aspirates from 48 infants (GA: 27.4+/-2.1 week, BW 959+/-334 g) during the first 12 postnatal days. RESULTS: Mean concentration of 6-keto-prostaglandinF(1 alpha) was 414+/-31 pg/ml (mean+/-S.E.M.), and of thromboxane B(2) was 418+/-37 pg/ml. Correlations existed between 6-keto-prostaglandinF(1 alpha) and gestational age, birth weight, and the initial arterial-alveolar oxygenation ratio. Negative correlations existed between 6-keto-prostaglandinF(1 alpha) and both mean inspiratory oxygen and duration of mechanical ventilation. Indomethacin treatment was associated with lower pulmonary 6-keto-prostaglandinF(1 alpha), but not with lower TxB(2). Thromboxane B(2) correlated positively with gestational age, birth weight, and initial arterial-alveolar oxygenation ratio, and inversely with duration of mechanical ventilation. CONCLUSIONS: In preterm infants, higher pulmonary 6-keto-prostaglandinF(1 alpha) was associated with less severe respiratory distress and with maturity, whereas thromboxane B(2) was associated more strongly with maturity than with respiratory distress.     

WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling

Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P₂] is a membrane lipid involved in several signaling pathways. However, the role of this lipid in the regulation of synapse growth is ill-defined. Here we identify PI(4,5)P₂ as a gatekeeper of neuromuscular junction (NMJ) size. We show that PI(4,5)P₂ levels in neurons are critical in restricting synaptic growth by localizing and activating presynaptic Wiscott-Aldrich syndrome protein/WASP (WSP). This function of WSP is independent of bone morphogenetic protein (BMP) signaling but is dependent on Tweek, a neuronally expressed protein. Loss of PI(4,5)P₂-mediated WSP activation results in increased formation of membrane-organizing extension spike protein (Moesin)-GFP patches that concentrate at sites of bouton growth. Based on pharmacological and genetic studies, Moesin patches mark polymerized actin accumulations and correlate well with NMJ size. We propose a model in which PI(4,5)P₂- and WSP-mediated signaling at presynaptic termini controls actin-dependent synapse growth in a pathway at least in part in parallel to synaptic BMP signaling.     

Intratumor versus intertumor heterogeneity in gene expression profiles of soft-tissue sarcomas

Soft-tissue sarcomas (STSs) constitute more than 30 histologic entities. In addition, within each entity, tumors are often heterogeneous in macroscopic features, genetic alterations, microscopic appearance, and clinical course. Therefore, there has been concern about whether a single tumor sample can provide a gene expression profile representative of the entire tumor. We used 27-k cDNA microarray slides to assess the importance of intratumor versus intertumor heterogeneity of the gene expression profiles of 2 morphologically heterogeneous STSs. Multiple pieces of tumor (8 and 10 pieces) were obtained from a myxoid variant of malignant fibrous histiocytoma (MFH) and a leiomyosarcoma (LMS), respectively, and the expression patterns were compared with single tumor samples from 20 MFHs and 16 LMSs. Hierarchical clustering analysis of the expression profiles showed that samples from the same tumor clustered together. The average intratumor distance was considerably shorter than the average intertumor distance in both LMS and MFH. In addition, tumor subclusters that distinguished different macroscopic parts of the tumor could be discerned. We concluded that intratumor variability exists but that accurate gene expression profiling also could be obtained using single samples from a large STS.     

Self-organized nanotubular oxide layers on Ti-6Al-7Nb and Ti-6Al-4V formed by anodization in NH4F solutions

The present work reports the fabrication of self-organized porous oxide-nanotube layers on the biomedical titanium alloys Ti-6Al-7Nb and Ti-6Al-4V by a simple electrochemical treatment. These two-phase alloys were anodized in 1M (NH(4))(2)SO(4) electrolytes containing 0.5 wt % of NH(4)F. The results show that under specific anodization conditions self-organized porous oxide structures can be grown on the alloy surface. SEM images revealed that the porous layers consist of arrays of single nanotubes with a diameter of 100 nm and a spacing of 150 nm. For the V-containing alloy enhanced etching of the beta phase is observed, leading to selective dissolution and an inhomogeneous pore formation. For the Nb-containing alloy an almost ideal coverage of both phases is obtained. According to XPS measurements the tubes are a mixed oxide with an almost stoichiometric oxide composition, and can be grown to thicknesses of several hundreds of nanometers. These findings represent a simple surface treatment for Ti alloys that has high potential for biomedical applications.     

In vivo evaluation of anodic TiO2 nanotubes: an experimental study in the pig

Because of their ability to mimic the dimensions of constituent components of natural bone and the possibility to serve as a gene and drug-delivery carrier, nanotubes seem to be a promising coating for medical implants. Aim of this study was to investigate the effects of a TiO(2) nanotube structured surface on periimplant bone formation in vivo when compared with an untreated standard titanium surface. Twenty-five titanium implants covered with an ordered TiO(2) nanotube layer with an individual tube diameter of 30 nm and 25 commercially pure titanium (cp-Ti) implants were placed in the frontal skull of 25 domestic pigs. To evaluate the effects of the nanotube structured implants on the periimplant bone formation, bone-implant contact (BIC), and immunohistochemistry analysis were performed at day 3, 7, 14, 30, and 90. Evaluating immunohistochemistry, a significantly higher collagen type- I expression occurred at day 7 (p = 0.003), day 14 (p = 0.016), and day 30 (p = 0.044), for the nanostructured implants in comparison with the control group. It could be found that a nanotube structured implant surface with a diameter of 30 nm does influence bone formation and bone development by enhancing osteoblast function. SEM evaluation of the specimen surfaces revealed that the nanotube coatings do resist shearing forces that evoked by implant insertion. Because of their simple, low cost, flexible manufacturing and the possibility for the usage as drug or growth factor delivery system, nanotubes seem to be a promising method for future medical implant coatings.     

Novel aspects of the molecular mechanisms controlling insulin secretion

Pancreatic β-cells secrete insulin by Ca²⁺-dependent exocytosis of secretory granules. β-cell exocytosis involves SNARE (soluble NSF-attachment protein receptor) proteins similar to those controlling neurotransmitter release and depends on the close association of L-type Ca²⁺ channels and granules. In most cases, the secretory granules fuse individually but there is ultrastructural and biophysical evidence of multivesicular exocytosis. Estimates of the secretory rate in β-cells in intact islets indicate a release rate of ∼15 granules per β-cell per second, 100-fold higher than that observed in biochemical assays. Single-vesicle capacitance measurements reveal that the diameter of the fusion pore connecting the granule lumen with the exterior is ∼1.4 nm. This is considerably smaller than the size of insulin and membrane fusion is therefore not obligatorily associated with release of the cargo, a feature that may contribute to the different rates of secretion detected by the biochemical and biophysical measurements. However, small molecules like ATP and GABA, which are stored together with insulin in the granules, are small enough to be released via the narrow fusion pore, which accordingly functions as a molecular sieve. We finally consider the possibility that defective fusion pore expansion accounts for the decrease in insulin secretion observed in pathophysiological states including long-term exposure to lipids.     

Face Perception in the Mind’s Eye

Perceptual filling-in occurs when visual stimuli are recognized in impoverished viewing conditions. Whether missing information is filled-in during face perception and which stages might be involved in this process are still unresolved questions. Because an identity can be brought to mind by seeing eyes only, we hypothesized that missing information might be filled-in from a memory trace for the whole face identity. We presented participants with faces in phase 1 and later we presented eyes-only in phase 2. For some of these eyes in phase 2, the whole face had been presented in the previous phase, for others identical eyes had been presented. Event-related potentials (ERPs) revealed an N170 component that was more negative when eyes were preceded by a whole face in the previous phase compared to eyes preceded by identical eyes-only. A more positive-going late positive complex (LPC) was also found, suggesting enhanced retrieval of face memory representations when eyes were preceded by whole faces. Our results show that pre-existing representations of face identity can influence early stages of visual encoding, 170 ms after stimulus onset. These effects may reflect top–down modulation by memory on visual recognition processes by filling-in the missing facial information.     

Genetic architecture of circulating lipid levels

Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.