Free-standing polyelectrolyte membranes made of chitosan and alginate

Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any postprocessing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side.This work was financially supported by Foundation for Science and Technology (FCT) through the Scholarship SFRH/BD/64601/2009 granted to S.G.C. C.M. is indebted to Grenoble INP for financial support via a postdoctoral fellowship. This work was supported by the European Commission (FP7 Program) via a European Research Council starting grant (BIOMIM, GA 259370 to C.P.). C.P. is also grateful to Institut Universitaire de France and to Grenoble Institute of Technology for financial support. We thank Isabelle Paintrand for her technical help with the confocal apparatus and Patrick Chaudouet for his help with SEM imaging

The role of birth weight on the causal pathway to child and adolescent ADHD symptomatology:a population-based twin differences longitudinal design

BackgroundAvailable evidence points towards lower birth weight as a risk factor for the development of attention deficit/hyperactivity disorder (ADHD) symptoms. We probed the causal nature of this putative effect of birth weight on ADHD symptoms using the twin differences design, which accounts for genetic and shared environmental confounds.MethodIn a large population‐based twin sample – 3,499 monozygotic (MZ) and 6,698 dizygotic (DZ) pairs – parents, teachers or twins rated the twins’ ADHD symptoms at nine assessment waves (2–16 years). We implemented the twin differences design, which completely accounts for shared environmental and genetic confounding in MZ twins. We tested whether: (a) the lighter‐born twins had elevated ADHD symptoms compared to the heavier‐born twins, by regressing within‐pair differences of ADHD symptoms on within‐pair differences of birth weight among MZ twins; (b) the effect of birth weight on ADHD was moderated by gender, gestational age and low birth weight; (c) this effect changed with age at ADHD assessment using adapted latent growth curve models; and (d) results differed for inattention and hyperactivity/impulsivity.ResultsBirth weight significantly predicted ADHD symptoms from early childhood to late adolescence. The lighter‐born twin had more ADHD symptoms than the heavier‐born cotwin among MZ twins across assessment waves and raters. No moderation effect was detected. The magnitude of the effect of birth weight decreased significantly across time for hyperactivity/impulsivity, but the decrease failed to reach significance for inattention. Estimates for inattention were significantly larger than for hyperactivity/impulsivity at each time point, implying stronger effect of birth weight on inattention symptoms.ConclusionsOur findings provide stringent evidence for environmental effect of lower birth weight on the causal pathway to elevated ADHD symptoms. Effect of birth weight persists across a 14‐year period from childhood into late adolescence, in particular for inattention symptoms.</p

Acquired resistance to DZNep-mediated apoptosis is associated with copy number gains of AHCY in a B-cell lymphoma model

BackgroundEnhancer of zeste homolog 2 (EZH2) is considered an important driver of tumor development and progression by its histone modifying capabilities. Inhibition of EZH2 activity is thought to be a potent treatment option for eligible cancer patients with an aberrant EZH2 expression profile, thus the indirect EZH2 inhibitor 3-Deazaneplanocin A (DZNep) is currently under evaluation for its clinical utility. Although DZNep blocks proliferation and induces apoptosis in different tumor types including lymphomas, acquired resistance to DZNep may limit its clinical application.MethodsTo investigate possible mechanisms of acquired DZNep resistance in B-cell lymphomas, we generated a DZNep-resistant clone from a previously DZNep-sensitive B-cell lymphoma cell line by long-term treatment with increasing concentrations of DZNep (ranging from 200 to 2000nM) and compared the molecular profiles of resistant and wild-type clones. This comparison was done using molecular techniques such as flow cytometry, copy number variation assay (OncoScan and TaqMan assays), fluorescence in situ hybridization, Western blot, immunohistochemistry and metabolomics analysis.ResultsWhole exome sequencing did not indicate the acquisition of biologically meaningful single nucleotide variants. Analysis of copy number alterations, however, demonstrated among other acquired imbalances an amplification (about 30 times) of the S-adenosyl-L-homocysteine hydrolase (AHCY) gene in the resistant clone. AHCY is a direct target of DZNep and is critically involved in the biological methylation process, where it catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine to L-homocysteine and adenosine. The amplification of the AHCY gene is paralleled by strong overexpression of AHCY at both the transcriptional and protein level, and persists upon culturing the resistant clone in a DZNep-free medium.ConclusionsThis study reveals one possible molecular mechanism how B-cell lymphomas can acquire resistance to DZNep, and proposes AHCY as a potential biomarker for investigation during the administration of EZH2-targeted therapy with DZNep

Development of wide range photon detection system for muonic X-ray spectroscopy

We have developed a photon detection system for muonic X-ray spectroscopy. The detector system consists of high-purity germanium detectors with BGO Compton suppressors. The signals from the detectors are readout with a digital acquisition system. The absolute energy accuracy, energy and timing resolutions, photo-peak efficiency, the performance of the Compton suppressor, and high count rate durability are studied with standard $\gamma$-ray sources and in-beam experiment using $^{27}\mathrm{Al}(p, \gamma){}^{28}\mathrm{Si}$ resonance reaction. The detection system was demonstrated at Paul Scherrer Institute. A calibration method for a photon detector at a muon facility using muonic X-rays of $^{197}$Au and $^{209}$Bi is proposed

Coulomb-blockade transport in single-crystal organic thin-film transistors

Coulomb-blockade transport—whereby the Coulomb interaction between electrons can prohibit their transport around a circuit—occurs in systems in which both the tunnel resistance, RT, between neighbouring sites is large (»h/e2) and the charging energy, EC (EC = e2/2C, where C is the capacitance of the site), of an excess electron on a site is large compared to kT. (Here e is the charge of an electron, k is Boltzmann's constant, and h is Planck's constant.) The nature of the individual sites—metallic, superconducting, semiconducting or quantum dot—is to first order irrelevant for this phenomenon to be observed. Coulomb blockade has also been observed in two-dimensional arrays of normal-metal tunnel junctions, but the relatively large capacitances of these micrometre-sized metal islands results in a small charging energy, and so the effect can be seen only at extremely low temperatures. Here we demonstrate that organic thin-film transistors based on highly ordered molecular materials can, to first order, also be considered as an array of sites separated by tunnel resistances. And as a result of the sub-nanometre sizes of the sites (the individual molecules), and hence their small capacitances, the charging energy dominates at room temperature. Conductivity measurements as a function of both gate bias and temperature reveal the presence of thermally activated transport, consistent with the conventional model of Coulomb blockade.

Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>The α₂-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an <it>in vitro </it>model for traumatic brain injury.</p> <p>Methods</p> <p>Organotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined.</p> <p>Results</p> <p>Dexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 μM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059.</p> <p>Conclusion</p> <p>In this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect.</p

Clinical and cost-effectiveness of contingency management for cannabis use in early psychosis: the CIRCLE randomised clinical trial

Background Cannabis is the most commonly used illicit substance amongst people with psychosis. Continued cannabis use following the onset of psychosis is associated with poorer functional and clinical outcomes. However, finding effective ways of intervening has been very challenging. We examined the clinical and cost-effectiveness of adjunctive contingency management (CM), which involves incentives for abstinence from cannabis use, in people with a recent diagnosis of psychosis. Methods CIRCLE was a pragmatic multi-centre randomised controlled trial. Participants were recruited via Early Intervention in Psychosis (EIP) services across the Midlands and South East of England. They had had at least one episode of clinically diagnosed psychosis (affective or non-affective); were aged 18 to 36; reported cannabis use in at least 12 out of the previous 24 weeks; and were not currently receiving treatment for cannabis misuse, or subject to a legal requirement for cannabis testing. Participants were randomised via a secure web-based service 1:1 to either an experimental arm, involving 12 weeks of CM plus a six-session psychoeducation package, or a control arm receiving the psychoeducation package only. The total potential voucher reward in the CM intervention was £240. The primary outcome was time to acute psychiatric care, operationalised as admission to an acute mental health service (including community alternatives to admission). Primary outcome data were collected from patient records at 18 months post-consent by assessors masked to allocation. The trial was registered with the ISRCTN registry, number ISRCTN33576045. Results Five hundred fifty-one participants were recruited between June 2012 and April 2016. Primary outcome data were obtained for 272 (98%) in the CM (experimental) group and 259 (95%) in the control group. There was no statistically significant difference in time to acute psychiatric care (the primary outcome) (HR 1.03, 95% CI 0.76, 1.40) between groups. By 18 months, 90 (33%) of participants in the CM group, and 85 (30%) of the control groups had been admitted at least once to an acute psychiatric service. Amongst those who had experienced an acute psychiatric admission, the median time to admission was 196 days (IQR 82, 364) in the CM group and 245 days (IQR 99, 382) in the control group. Cost-effectiveness analyses suggest that there is an 81% likelihood that the intervention was cost-effective, mainly resulting from higher mean inpatient costs for the control group compared with the CM group; however, the cost difference between groups was not statistically significant. There were 58 adverse events, 27 in the CM group and 31 in the control group. Conclusions Overall, these results suggest that CM is not an effective intervention for improving the time to acute psychiatric admission or reducing cannabis use in psychosis, at least at the level of voucher reward offered