A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin

YesUnderstanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 °C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7-hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm2/h) range in eighty-seven individuals. Glutathione conjugation (GST) of 1-chloro-2,4-dinitrobenzene was assessed in a smaller pool of fifty donors; the metabolic rate was much faster and measured over six minutes using a different methodology to express rates in μg/mg protein/min (converted to μg/cm2/min). A comprehensive statistical analysis of these results was carried out, separating donors by age, gender and metabolic rate measured

Supramolecular approach to new inkjet printing inks

Electronically complementary, low molecular weight polymers that self-assemble through tunable π−π stacking interactions to form extended supramolecular polymer networks have been developed for inkjet printing applications and successfully deposited using three different printing techniques. Sequential overprinting of the complementary components results in supramolecular network formation through complexation of π-electron rich pyrenyl or perylenyl chain-ends in one component with π-electron deficient naphthalene diimide residues in a chain-folding polyimide. The complementary π−π stacked polymer blends generate strongly colored materials as a result of charge-transfer absorption bands in the visible spectrum, potentially negating the need for pigments or dyes in the ink formulation. Indeed, the final color of the deposited material can be tailored by varying the end-groups of the π-electron rich polymer component. Piezoelectric printing techniques were employed in a proof of concept study to allow characterization of the materials deposited, and a thermal inkjet printer adapted with imaging software enabled in situ analysis of the ink drops as they formed and of their physical properties. Finally, continuous inkjet printing allowed greater volumes of material to be deposited, on a variety of different substrate surfaces, and demonstrated the utility and versatility of this novel type of ink for industrial applications

Unseeded Elastomeric Single Leaflets Retain Function and Remodel After Implant In Ovine Pulmonary Outflow Tract

Current materials for heart valve replacement and repair are limited by the inability to grow or remodel. Tissue engineered valves offer the potential to overcome these disadvantages by creating living structures, but is limited by the availability of biocompatible scaffold materials with desirable biomechanical properties. We assessed the in vivo performance of a novel scaffold poly(carbonate urethane) urea (PCUU), fabricated by electrospinning and implanted in the pulmonary outflow tract of sheep. PCUU was electrospun into elastomeric sheets of thickness ranging from 120-180 μm. Using cardiopulmonary bypass we replaced the native anterior pulmonary leaflet with an acellular PCUU leaflet. Valve function was evaluated by epicardial echocardiography at implant and explant at weeks 1 (n=3), 3 (n=3), 6 (n=3) and 16 (n=3). Histological, immunohistochemical, molecular imaging analyses and multi-photon imaging were performed on the explanted leaflets. Echocardiography demonstrated mobile functioning leaflets, with zero to mild pulmonary regurgitation. Molecular imaging showed increased levels of proteolytic activity and macrophage accumulation. Histology showed persistence of scaffold material up to 16 weeks with cellular infiltration throughout the leaflet. Picrosirius red revealed mature collagen deposition along the arterial surface of the construct at 6 and 16 weeks. These findings were corroborated by multi-photon analysis showing highly aligned collagen fibers across the leaflets. Both surfaces of the engineered leaflets were consistently covered with CD31 positive cells. The majority of cells expressed α-SMA and MMP2. CD45 positive cells, suggesting hematogenous origin, were found throughout the leaflet. These results suggest that: 1) PCUU can be a suitable polymer for valve bioengineering; 2) cell pre-seeding may not be required for tissue formation or remodeling for a functional engineered valve; 3) host cells seem to populate the leaflet either by migration from adjacent tissue or by attachment from circulating blood; 4) mature matrix orientation and increased proteolytic activity suggests active tissue remodeling. Longer term implants and the role of scaffold pre-seeding will require further study

Three Keys to Success for Principals (and Their Teachers)

This is the author's accepted manuscript, post peer-review. The publisher's official version is available at: http://dx.doi.org/10.1080/00228958.2008.10516527.What is successful leadership and how can leadership concepts be applied to schools? Hundreds of books and articles and a plethora of executive seminars describe what leadership is and propose strategies for what effective leaders do. Most of these writings and presentations, however, focus on business, with much less information available about how to lead schools. In addition, there is a diversity of opinions about what makes leaders effective. This article suggests that it is possible to extract, reframe, and apply the best of what is known about leadership to help principals be more successful. Moreover, if principals are successful, teachers also are positioned to be successful, with the ultimate impact being successful student learning

Environmental Effects Dominate the Folding of Oligocholates in Solution, Surfactant Micelles, and Lipid Membranes

Oligocholate foldamers with different numbers and locations of guanidinium−carboxylate salt bridges were synthesized. The salt bridges were introduced by incorporating arginine and glutamic acid residues into the foldamer sequence. The conformations of these foldamers were studied by fluorescence spectroscopy in homogeneous solution, anionic and nonionic micelles, and lipid bilayers. Environmental effects instead of inherent foldability were found to dominate the folding. As different noncovalent forces become involved in the conformations of the molecules, the best folder in one environment could turn into the worst in another. Preferential solvation was the main driving force for the folding of oligocholates in solution. The molecules behaved very differently in micelles and lipid bilayers, with the most critical factors controlling the folding−unfolding equilibrium being the solvation of ionic groups and the abilities of the surfactants/lipids to compete for the salt bridge. Because of their ability to fold into helices with a nonpolar exterior and a polar interior, the oligocholates could transport large hydrophilic molecules such as carboxyfluorescein across lipid bilayers. Both the conformational properties of the oligocholates and their binding with the guest were important to the transport efficiency.Reprinted (adapted) with permission from Journal of the American Chemical Society 132 (2010): 9890, doi:10.1021/ja103694p. Copyright 2010 American Chemical Society.</p