Laboratory and Field Studies of Insecticide Impregnated Fibres for Mosquito Control

Laboratory and field studies were undertaken in an attempt to improve mosquito control with insecticide-treated fabrics. The efficacies of the emulsifiable concentrates (E.C.) of three pyrethroids were assessed on three types of fibre in order to establish the optimum combination for bednet use. Various pyrethroid formulations were compared for persistence and wash-fastness. Incorporation of polystyrene into the E.C. of permethrin increased its wash-resistance. Scanning electron microscope studies revealed a film of permethrin on impregnated nylon fibre which was not visible on similarly impregnated cotton fibre. Using an acoustic actograph to record flight activity and video to record behaviour, impregnated nylon was found to cause greater irritancy than impregnated cotton. The contact times for mosquitoes to pick-up lethal doses from permethrin and lambdacyhalothrin treated netting were established and related to the time that a hungry mosquito spends searching for a bloodmeal. Studies on sublethal effects of treated netting such as knock-down, leg fracture and feeding inhibition were carried out. Experimental hut trials of bednets were undertaken in The Gambia to compare five different insecticides, an insecticide mixture and two formulations incorporating polystyrene. The unwashed permethrin formulations strongly deterred hut entry by An.gambiae s.l. and Mansonia spp. but this effect was lost after washing the nets three times. The unwashed insecticide-treated nets killed a significantly higher percentage of An.gambiae s.l. that entered the huts than the untreated net. Washing treated nets decreased the percentages killed by them, with the exception of the wash-resistant permethrin which showed no significant change in the percentage of mosquitoes killed. This formulation killed a significantly higher percentage than the normal permethrin formulation after washing. The unwashed mixture of permethrin and pirimiphos-methyl treated net performed well over the 6 weeks of the trial, but chemical analyses at the end of this time showed very little of its pirimiphos-methyl remained on the net. The effects of all the nets on numbers entering and exiting from huts and numbers found killed and bloodfed are reported. A trial was carried out in a village to compare nets treated with the wash- resistant formulation of permethrin, normal E.C.s of permethrin and lambdacyhalothrin and placebo. The numbers of mosquitoes found over 16 weeks during weekly bednet searches of the insecticide treated nets were greatly reduced compared with the placebo treated nets. Analysis of bioassay mortality showed that the permethrin formulation containing polystyrene (wash-resistant) was significantly less affected by washing under village conditions than the normal permethrin and lambdacyhalothrin formulations

Increased artery wall stress post-stenting leads to greater intimal thickening

Since the first human procedure in the late 1980s, vascular stent implantation has been accepted as a standard form of treatment of atherosclerosis. Despite their tremendous success, these medical devices are not without their problems, as excessive neointimal hyperplasia can result in the formation of a new blockage (restenosis). Clinical data suggest that stent design is a key factor in the development of restenosis. Additionally, computational studies indicate that the biomechanical environment is strongly dependent on the geometrical configuration of the stent, and therefore possibly involved in the development of restenosis. We hypothesize that stents that induce higher stresses on the artery wall lead to a more aggressive pathobiologic response, as determined by the amount of neointimal hyperplasia. The aim of this investigation was to examine the role of solid biomechanics in the development of restenosis. A combination of computational modeling techniques and in vivo analysis were employed to investigate the pathobiologic response to two stent designs that impose greater or lesser levels of stress on the artery wall. Stent designs were implanted in a porcine model (pigs) for approximately 28 days and novel integrative pathology techniques (quantitative micro-computed tomography, histomorphometry) were utilized to quantify the pathobiologic response. Concomitantly, computational methods were used to quantify the mechanical loads that the two stents place on the artery. Results reveal a strong correlation between the computed stress values induced on the artery wall and the pathobiologic response; the stent that subjected the artery to the higher stresses had significantly more neointimal thickening at stent struts (high stress stent: 0.197 ± 0.020 mm vs. low-stress stent: 0.071 ± 0.016 mm). Therefore, we conclude that the pathobiologic differences are a direct result of the solid biomechanical environment, confirming the hypothesis that stents that impose higher wall stresses will provoke a more aggressive pathobiological response

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 μg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 μg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT

Lobeline Attenuates the Locomotor-Activating Properties of Repeated Morphine Treatment in Rats

Purpose: Lobeline perturbs intra- and extracellular neurotransmitter levels and diminishes the in vitro and in vivo effects of psychostimulants. More recently, lobeline was shown to bind to μ opiate receptors, block the effects of opiate receptor agonists, and decrease heroin self-administration in rats. The present study determined the effect of lobeline on morphine-induced changes in locomotor behavior in rats.Methods: For 12 consecutive days (Days 1 - 12), male rats were administered lobeline (0.3 or 1 mg/kg) followed by morphine (5 or 10 mg/kg) and locomotor activity was measured. On Day 13, the effect of lobeline on the expression of morphine-induced increases in activity was determined.Results: With repeated morphine treatment, an increase in locomotor  activity was observed. In a dosedependent manner, lobeline decreased the morphine-induced increase in activity. Acute lobeline challenge on Day 13 also attenuated the expression of this morphine-induced increase in activity.                                                                               Conclusion: These results are consistent with previous work where lobeline blocks the locomotoractivtating properties of psychostimulants, and these findings support an emerging literature suggesting that lobeline produces its behavioral effects through an interaction with μ opiate receptors.Keywords: Behavior, Morphine, Locomotor activity, Behavioural sensitization, μ Opiate receptor

Human osteoblasts within soft peptide hydrogels promote mineralisation in vitro

Biomaterials that provide three-dimensional support networks for the culture of cells are being developed for a wide range of tissue engineering applications including the regeneration of bone. This study explores the potential of the versatile ionic-complementary peptide, FEFEFKFK, for such a purpose as this peptide spontaneously self-assembles into β-sheet-rich fibres that subsequently self-associate to form self-supporting hydrogels. Via simple live/dead cell assays, we demonstrated that 3 wt% hydrogels were optimal for the support of osteoblast cells. We went on to show that these cells are not only viable within the three-dimensional hydrogel but they also proliferate and produce osteogenic key proteins, that is, they behave like in vivo bone cells, over the 14-day period explored here. The gel elasticity increased over time when cells were present – in comparison to a decrease in control samples – indicating the deposition of matrix throughout the peptide scaffold. Moreover, significant quantities of calcium phosphate were deposited. Collectively, these data demonstrate that ionic-complementary octapeptides offer a suitable three-dimensional environment for osteoblastic cell function

K-Bayes Reconstruction for Perfusion MRI II: Modeling and Technical Development

Despite the continued spread of magnetic resonance imaging (MRI) methods in scientific studies and clinical diagnosis, MRI applications are mostly restricted to high-resolution modalities such as structural MRI. While perfusion MRI gives complementary information on blood flow in the brain, its reduced resolution limits its power for detecting specific disease effects on perfusion patterns. This reduced resolution is compounded by artifacts such as partial volume effects, Gibbs ringing, and aliasing, which are caused by necessarily limited k-space sampling and the subsequent use of discrete Fourier transform (DFT) reconstruction. Here, a Bayesian modeling procedure (K-Bayes) is developed for the reconstruction of perfusion MRI. The K-Bayes approach combines a process model for the MRI signal in k-space with a Markov random field prior distribution that incorporates high-resolution segmented structural MRI information. A simulation study, described in Part I (Concepts and Applications), was performed to determine qualitative and quantitative improvements in K-Bayes reconstructed images compared with those obtained via DFT. The improvements were validated using in vivo perfusion MRI data of the human brain. The K-Bayes reconstructed images were demonstrated to provide reduced bias, increased precision, greater effect sizes, and higher resolution than those obtained using DFT

Future X-ray timing missions

Thanks to the Rossi X-ray Timing Explorer (RXTE), it is now widely recognized that fast X-ray timing can be used to probe strong gravity fields around collapsed objects and constrain the equation of state of dense matter in neutron stars. We first discuss some of the outstanding issues which could be solved with an X-ray timing mission building on the great successes of RXTE and providing an order of magnitude better sensitivity. Then we briefly describe the 'Experiment for X-ray timing and Relativistic Astrophysics' (EXTRA) recently proposed to the European Space Agency as a follow-up to RXTE and the related US mission 'Relativistic Astrophysics Explorer' (RAE).Comment: To be published in `Proceedings of the Third Microquasar Workshop: Granada Workshop on galactic relativistic jet sources', Eds A. J. Castro-Tirado, J. Greiner and J. M. Paredes, Astrophysics and Space Science, in press. More about EXTRA can be found at: http://www.cesr.fr/~barret/extra.htm

Enrichment of Two Isomeric Heparin Oligosaccharides Exhibiting Different Affinities toward Monocyte Chemoattractant Protein-1

Chemokine-GAG interactions are crucial to facilitate chemokine immobilization, resulting in the formation of chemokine gradients that guide cell migration. Here we demonstrate chromatographic isolation and purification of two heparin hexasaccharide isomers that interact with the oligomeric chemokine Monocyte Chemoattractant Protein-1 (MCP-1)/CCL2 with different binding affinities. The sequences of these two hexasaccharides were deduced from unique MS/MS product ions and HPLC compositional analysis. Ion mobility mass spectrometry (IM-MS) showed that the two isolated oligosaccharides have different conformations and both displayed preferential binding for one of the two distinct conformations known for MCP-1 dimers. A significant shift in arrival time distribution of close to 70 Å2 was observed, indicating a more compact protein:hexasaccharide conformation. Clear differences in the MS spectra between bound and unbound protein allowed calculation of Kd values from the resulting data. The structural difference between the two hexasaccharides was defined as the differential location of a single sulfate at either C-6 of glucosamine or C-2 of uronic acid in the reducing disaccharide, resulting in a 200-fold difference in binding affinity for MCP-1. These data indicate sequence specificity for high affinity binding, supporting the view that sulfate position, and not simply the number of sulfates, is important for heparan sulfate protein binding

Heparin Isomeric Oligosaccharide Separation Using Volatile Salt Strong Anion Exchange Chromatography

The complexity of heparin and heparan sulfate saccharides makes their purification, including many isomeric structures, very challenging and is a bottleneck for structure–activity studies. High-resolution separations have been achieved by strong anion exchange (SAX) chromatography on Propac PA1 and cetyltrimethylammonium (CTA)-C18 silica columns; however, these entail subsequent desalting methodologies and consequent sample losses and are incompatible with orthogonal chromatography methodologies and, in particular, mass spectrometry. Here, we present the CTA-SAX purification of heparin oligosaccharides using volatile salt (VS) buffer. In VSCTA-SAX, the use of ammonium bicarbonate buffer for elution improves resolution through both weaker dissociation and conformational coordination of the ammonium across the sulfate groups. Using ion mobility mass spectrometry, we demonstrate that isomeric structures have different structural conformations, which makes chromatographic separation achievable. Resolution of such structures is improved compared to standard SAX methods, and in addition, VSCTA-SAX provides an orthogonal method to isolate saccharides with higher purity. Because ammonium bicarbonate is used, the samples can be evaporated rather than desalted, preventing substantial sample loss and allowing more effective subsequent analysis by electrospray mass spectrometry. We conclude that VSCTA-SAX is a powerful new tool that helps address the difficult challenge of heparin/heparan sulfate saccharide separation and will enhance structure–activity studies