A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration

Language and social/emotional problems identified at a universal developmental assessment at 30 months

Non peer reviewedPublisher PD

The "silver" Japanese quail and the MITF gene: causal mutation, associated traits and homology with the "blue" chicken plumage

<p>Abstract</p> <p>Background</p> <p>The <it>MITF </it>(<it>microphthalmia-associated transcription factor</it>) gene has been investigated in mice and various vertebrates but its variations and associated effects have not yet been explored much in birds. The present study describes the causal mutation <it>B </it>at the <it>MITF </it>gene responsible for the "silver" plumage colour in the Japanese quail (<it>Coturnix japonica</it>), and its associated effects on growth and body composition, and tests its allelism with the "blue" plumage colour mutation <it>Bl </it>in <it>Gallus gallus</it>.</p> <p>Results</p> <p>The semi dominant <it>B </it>mutation results from a premature stop codon caused by a 2 bp deletion in exon 11 of <it>MITF</it>. Homozygous "white" (<it>B/B</it>) quail which have a white plumage also show a slightly lower growth, lower body temperature, smaller heart, and lighter <it>pectoralis </it>muscles but more abdominal adipose tissue than the recessive homozygous "wild-type" (<it>+/+</it>) and heterozygous "silver" (<it>B/+</it>) quail. Similar observations on cardiac and body growth were made on mice (<it>Mus musculus</it>) homozygous for mutations at <it>MITF</it>. The production of chicken-quail hybrids with a white plumage obtained by crossing <it>Bl/+ </it>chicken heterozygous for the <it>blue </it>mutation with <it>B/B </it>white quail indicated that the mutations were allelic.</p> <p>Conclusion</p> <p>The "silver" Japanese quail is an interesting model for the comparative study of the effects of <it>MITF </it>in birds and mammals. Further investigation using a chicken family segregating for the "blue" plumage and molecular data will be needed to confirm if the "blue" plumage in chicken results from a mutation in <it>MITF</it>.</p

Convergent genetic linkage and associations to language, speech and reading measures in families of probands with Specific Language Impairment

We analyzed genetic linkage and association of measures of language, speech and reading phenotypes to candidate regions in a single set of families ascertained for SLI. Sib-pair and family-based analyses were carried out for candidate gene loci for Reading Disability (RD) on chromosomes 1p36, 3p12-q13, 6p22, and 15q21, and the speech-language candidate region on 7q31 in a sample of 322 participants ascertained for Specific Language Impairment (SLI). Replication or suggestive replication of linkage was obtained in all of these regions, but the evidence suggests that the genetic influences may not be identical for the three domains. In particular, linkage analysis replicated the influence of genes on chromosome 6p for all three domains, but association analysis indicated that only one of the candidate genes for reading disability, KIAA0319, had a strong effect on language phenotypes. The findings are consistent with a multiple gene model of the comorbidity between language impairments and reading disability and have implications for neurocognitive developmental models and maturational processes

Clinicians’ response to hyperoxia in ventilated patients in a Dutch ICU depends on the level of FiO2

Hyperoxia may induce pulmonary injury and may increase oxidative stress. In this retrospective database study we aimed to evaluate the response to hyperoxia by intensivists in a Dutch academic intensive care unit. All arterial blood gas (ABG) data from mechanically ventilated patients from 2005 until 2009 were extracted from an electronic storage database of a mixed 32-bed intensive care unit in a university hospital in Amsterdam. Mechanical ventilation settings at the time of the ABG tests were retrieved. The results of 126,778 ABG tests from 5,498 mechanically ventilated patients were retrieved including corresponding ventilator settings. In 28,222 (22%) of the ABG tests the arterial oxygen tension (PaO2) was > 16 kPa (120 mmHg). In only 25% of the tests with PaO2 > 16 kPa (120 mmHg) was the fraction of inspired oxygen (FiO(2)) decreased. Hyperoxia was accepted without adjustment in ventilator settings if FiO(2) was 0.4 or lower. Hyperoxia is frequently seen but in most cases does not lead to adjustment of ventilator settings if FiO(2) <0.41. Implementation of guidelines concerning oxygen therapy should be improved and further research is needed concerning the effects of frequently encountered hyperoxi

Feasibility of Modified Surviving Sepsis Campaign Guidelines in a Resource-Restricted Setting Based on a Cohort Study of Severe S. Aureus Sepsis

[This corrects the article on p. e29858 in vol. 7.]

Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane

Poly-(γ-l-glutamylglutamine)–paclitaxel (PGG–PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked to the polymer via ester bonds. PGG–PTX is of interest because it spontaneously forms very small nanoparticles in plasma. In mouse models, PGG–PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor. In this study, the efficacy of PGG–PTX was compared to that of Abraxane, an established nanoparticular formulation of PTX, in three different tumor models. Efficacy was quantified by delay in tumor growth of NCI H460 human lung cancer, 2008 human ovarian cancer and B16 melanoma xenografts growing in athymic mice following administration of equitoxic doses of PGG–PTX and Abraxane administered on either a single dose or every 7 day schedule. Toxicity was assessed by change in total body weight. The efficacy and toxicity of PGG–PTX was shown to increase with dose in the H460 model. PGG–PTX was ~1.5-fold less potent than Abraxane. PGG–PTX produced statistically significantly greater inhibition of tumor growth than Abraxane in all three tumor models when mice were given single equitoxic doses of drug. When given every 7 days for 3 doses, PGG–PTX produced greater inhibition of tumor growth while generating much less weight loss in mice bearing H460 tumors. PGG–PTX has activity that is superior to that of Abraxane in multiple tumor models. PGG–PTX has the potential to out-perform Abraxane in enhancing the delivery of PTX tumors while at the same time further reducing the toxicity of both single dose and weekly treatment regimens