A low molecular weight hydro and organogelator derived from an isohexide and sol-gel transcription of the alcogel

Heating 2,5-di-O-methanesulfonyl-1,4:3,6-dianhydro-D-sorbitol (1) in a range of solvents led to the formation of a gel state at low concentrations. 1 was found to gel aromatics, alcohols and water. The structure of 1 in the solid state was solved by single crystal X-ray crystallography; no strong hydrogen bonds or associated solvents were found in the crystal. Electron micrographs revealed the morphology of the gels to be predominantly rod-like. The ethanol alcogel was used to template silica by sol-gel transcription.

Effect of pioglitazone on endothelial function in impaired glucose tolerance

Aim: Flow-mediated dilation (FMD) is a surrogate marker of endothelial function, which has been proposed as a barometer of vascular health. Impaired microvascular response to reactive hyperaemia is thought to be the mechanism behind reduced shear stress and subsequently impaired FMD, which has been associated with cardiovascular events. This study aims to assess the effect of pioglitazone on the vasculature of patients with impaired glucose tolerance (IGT).

Materials and Methods: Forty IGT patients with no cardiovascular disease were compared with 24 healthy age- and sex-matched controls. Endothelial function was assessed using FMD of the brachial artery. Adiponectin (ADN) levels were measured and insulin sensitivity was calculated using homeostasis model assessment of insulin resistance (HOMA-IR). A randomised double-blind placebo-controlled trial of the IGT subjects was then performed, with subjects receiving either pioglitazone 30 mg od or matched placebo for 12 weeks before the measurements were repeated.

Results: The IGT subjects had a significantly impaired FMD compared with the controls (p < 0.001). Diastolic shear stress (DSS) was also significantly reduced in IGT (p = 0.04). High molecular weight (HMW) ADN was significantly lower in the IGT group than in controls (p = 0.03). On analysis of the IGT group after 12 weeks treatment, FMD was significantly increased in the pioglitazone group compared with placebo (p = 0.03) as was endothelium-independent dilation (EID) (p = 0.03). A significant increase in total ADN (p < 0.001), HMW ADN (p < 0.001) and HMW/total ratio (p = 0.001) occurred in the pioglitazone group compared with placebo.

Conclusions: Pioglitazone improved endothelial function in IGT. Treatment with pioglitazone may reduce the risk of cardiovascular disease in this patient group.

Assessment of a multiplexing high throughput immunochemical SPR biosensor in measuring multiple proteins on a single biosensor chip

Multiplexed immunochemical detection platforms offer the potential to decrease labour demands, increase sample throughput and decrease overall time to result. A prototype four channel multiplexed high throughput surface plasmon resonance biosensor was previously developed, for the detection of food related contaminants. A study focused on determining the instruments performance characteristics was undertaken. This was followed by the development of a multiplexed assay for four high molecular weight proteins. The protein levels were simultaneously evaluated in serum samples of 10-week-old veal calves (n = 24) using multiple sample preparation methods. Each of the biosensor's four channels were shown to be independent of one another and produced multiplexed within run repeatability (n = 6) ranging from 2.0 to 6.7%CV, for the four tested proteins, whilst between run reproducibility (n = 4) ranged from 1.5 to 8.9%CV. Four calibration curves were successfully constructed before serum sample preparation was optimised for each protein. Multiplexed concentration analysis was successfully performed on four channels revealing that each proteins concentration was consistent across the twenty-four tested animals. Signal reproducibility (n > 19) on a further long term study revealed coefficient of variation ranging from 1.1% to 7.3% and showed that the multiplexed assay was stable for at least 480 cycles. These findings indicate that the performance characteristics fall within the range of previously published data for singleplex optical biosensors and that the multiplexing biosensor is fit-for-purpose for simultaneous concentration analysis in many different types of applications such as the multiplexed detection of markers of growth-promoter abuse and multiplexed detection of residues of concern in food safety. © 2013 Elsevier B.V.

An evaluation of the capability of a biolayer interferometry biosensor to detect low-molecular-weight food contaminants

The safety of our food is an essential requirement of society. One well-recognised threat is that of chemical contamination of our food, where low-molecular-weight compounds such as biotoxins, drug residues and pesticides are present. Low-cost, rapid screening procedures are sought to discriminate the suspect samples from the population, thus selecting only these to be forwarded for confirmatory analysis. Many biosensor assays have been developed as screening tools in food contaminant analysis, but these tend to be electrochemical, fluorescence or surface plasmon resonance based. An alternative approach is the use of biolayer interferometry, which has become established in drug discovery and life science studies but is only now emerging as a potential tool in the analysis of food contaminants. A biolayer interferometry biosensor was assessed using domoic acid as a model compound. Instrument repeatability was tested by simultaneously producing six calibration curves showing replicate repeatability (n = 2) ranging from 0.1 to 6.5 % CV with individual concentration measurements (n = 12) ranging from 4.3 to 9.3 % CV, giving a calibration curve midpoint of 7.5 ng/ml (2.3 % CV (n = 6)). Reproducibility was assessed by producing three calibration curves on different days, giving a midpoint of 7.5 ng/ml (3.4 %CV (n = 3)). It was further shown, using assay development techniques, that the calibration curve midpoint could be adjusted from 10.4 to 1.9 ng/ml by varying assay parameters before the simultaneous construction of three calibration curves in matrix and buffer. Sensitivity of the assay compared favourably with previously published biosensor data for domoic acid. © 2013 Springer-Verlag Berlin Heidelberg.

Microabrasion : A novel method to assess surface degradation of UHMWPE following sterilisation and ageing

The ageing behaviour of ultra-high molecular weight polyethylene (UHMWPE) has been studied following gamma irradiation (25 or 40 kGy) in air. Accelerated ageing procedures used elevated temperature (70°C) and/or pressurised oxygen (5 bar). Shelf-aged UHMWPE was also studied. The variation in surface density and mechanical properties were determined following the various sterilisation and ageing treatments. Microabrasive wear testing was also performed. Wear rates were found to correlate well with stress at break for sterilised and aged UHMWPE but not with elongation to failure. It is proposed that the wear mechanism is fracture dominated and occurs following some disentanglement of the polymer chains. Wear also depends upon embrittlement of the surface layer due to its processing and ageing. Elongation to failure in a tensile test is not a good measure of this embrittlement whereas the microabrasion test provides more surface sensitive information concerning this property.

Co-melt fluidised bed granulation of pharmaceutical powders: Improvements in drug bioavailability

This study investigates the use of co-melt fluidised bed granulation for the agglomeration of model pharmaceutical powders, namely, lactose mono-hydrate, PEG 10000, poly-vinyl pyrolidone and ibuprofen as a model drug. Granulation within the co-melt system was found to follow a nucleationâ??steady growthâ??coating regime profile. Using high molecular weight PEG binder, the granulation mechanism and thus the extent of granulation was found to be significantly influenced by binder viscosity. The compression properties of the granulate within the hot fluidised bed were correlated using a novel high temperature experimental procedure. It was found that the fracture stress and fractural modulus of the materials under hot processing conditions were orders of magnitude lower than those measured under ambient conditions. A range of particle velocities within the granulator were considered based on theoretical models. After an initial period of nucleation, the Stokes deformation number analysis indicated that only velocities within the high shear region of the fluidised bed were sufficient to promote significant granule deformation and therefore, coalescence. The data also indicated that larger granules de-fluidised preventing agglomeration by coalescence. Furthermore, experimental data indicated that dissipation of the viscous molten binder to the surface was the most important factor in the latter stages of the granulation process. From a pharmaceutical perspective the inclusion of the model drug, ibuprofen, combined with PVP in the co-melt process proved to be highly significant. It was found that using DSC analysis on the formulations that the decrease in the heat of fusion associated with the melting of ibuprofen within the FHMG systems may be attributed to interaction between PVP and ibuprofen through inter-molecular hydrogen bonding. This interaction decreases the crystallinity of ibuprofen and facilitates solubilisation and bioavailability within the solid matrix.

Equilibrium polymerization of cyclic carbonate oligomers. III. Chain branching and the gel transition

Ring-opening polymerization of cyclic polycarbonate oligomers, where monofunctional active sites act on difunctional monomers to produce an equilibrium distribution of rings and chains, leads to a "living polymer." Monte Carlo simulations [two-dimensional (2D) and three-dimensional (3D)] of the effects of single [J. Chem. Phys. 115, 3895 (2001)] and multiple active sites [J. Chem. Phys. 116, 7724 (2002)] are extended here to trifunctional active sites that lead to branching. Low concentrations of trifunctional particles c(3) reduce the degree of polymerization significantly in 2D, and higher concentrations (up to 32%) lead to further large changes in the phase diagram. Gel formation is observed at high total density and sizable c(3) as a continuous transition similar to percolation. Polymer and gel are much more stable in 3D than in 2D, and both the total density and the value of c(3) required to produce high molecular weight aggregates are reduced significantly. The degree of polymerization in high-density 3D systems is increased by the addition of trifunctional monomers and reduced slightly at low densities and low c(3). The presence of branching makes equilibrium states more sensitive (in 2D and 3D) to changes in temperature T. The stabilities of polymer and gel are enhanced by increasing T, and-for sufficiently high values of c(3)-there is a reversible polymer-gel transformation at a density-dependent floor temperature. (C) 2002 American Institute of Physics.

Enhanced surface attachment of protein-type targeting ligands to poly(lactide-co-glycolide) nanoparticles using variable expression of polymeric acid functionality

The density of reactive carboxyl groups on the surface of poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) was modulated using a combination of high-molecular weight (MW) encapped and low MW non-encapped PLGA. Carboxyl groups were activated using carbodiimide chemistry and conjugated to bovine serum albumin and a model polyclonal antibody. Activation of carboxyl,groups in solution-phase PLGA prior to NP formation was compared with a postformation activation of peripheral carboxyl groups on intact NP. Activation before or after NP formation did not influence conjugation efficiency to NP prepared using 100% of the low-MW PLGA. The effect of steric stabilization using poly(vinyl alcohol) reduced conjugation of a polyclonal antibody from 62 mu g/(mg NP) to 32 mu g/(mg NP), but enhanced particulate stability. Increasing the amount of a high-MW PLGA also reduced Conjugation, with the activation post-formation still superior to the preformation approach. Drug release studies showed that high proportions of high-MW PLGA in the NP produced a longer sustained release profile of a model drug (celecoxib). It can be concluded that activating intact PLGA NP is superior to activating component parts prior to NP formation. Also, high MW PLGA could be used to prolong drug release, but at the expense of conjugation efficiency on to the NP surface. (C) 2008 Wiley Periodicals, Inc. J Biomed Mater Res 87A: 873-884, 2008

Characterization of melanoidins from a glucose-glycine model system

The properties of melanoidins prepared from glucose and glycine (GG) were investigated by a three step purification protocol consisting of dialysis, gel filtration at high ionic strength and ion metal affinity chromatography. The high molecular weight fraction obtained in the GG system is responsible for 80% of the total brown colour and its antioxidative ability was about 1/4 of that of Trolox measured by the inhibition of linoleic acid oxidation. GG melanoidins have good affinity towards Cu (II) (32% bound to the resin) while it is much lower towards Pb (II) (10%) and Fe (II) (5%). Capillary zone electrophoresis analysis suggests that GG melanoidins are positively charged, although no signal was observed analysing melanoidins by matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF/MS).

Activation of the epidermal growth factor receptor (EGFR) by a novel metalloprotease pathway

Neutrophil Elastase (NE) is a pro-inflammatory protease present at higher than normal levels in the lung during inflammatory disease. NE regulates IL-8 production from airway epithelial cells and can activate both EGFR and TLR4. TACE/ADAM17 has been reported to trans-activate EGFR in response to NE. Here, using 16HBE14o-human bronchial epithelial cells we demonstrate a new mechanism by which NE regulates both of these events. A high molecular weight soluble metalloprotease activity detectable only in supernatants from NE-treated cells by gelatin and casein zymography was confirmed to be meprin alpha by Western immunoblotting. In vitro studies demonstrated the ability of NE to activate meprin alpha, which in turn could release soluble TGFa and induce IL-8 production from 16HBE14o- cells. These effects were abrogated by actinonin, a specific meprin inhibitor. NE-induced IL-8 expression was also inhibited by meprin alpha siRNA. Immunoprecipitation studies detected EGFR/TLR4 complexes in NE-stimulated cells overexpressing these receptors. Confocal studies confirmed colocalization of EGFR and TLR4 in 16HBE14o- cells stimulated with meprin alpha. NF?B was also activated via MyD88 in these cells by meprin alpha. In bronchoalveolar lavage fluid from NE knock-out mice infected intra-tracheally with Pseudomonas aeruginosa meprin alpha was significantly decreased compared with control mice, and was significantly increased and correlated with NE activity, in bronchoalveolar lavage fluid from individuals with cystic fibrosis but not healthy controls. The data describe a previously unidentified lung metalloprotease meprin alpha, and its role in NE-induced EGFR and TLR4 activation and IL-8 production.