Adverse reactions to drugs: in vitro studies with isolated cells

Objective and design: Drug-induced adverse reactions can be allergic or pseudoallergic in nature, in this study the histamine releasing ability of 4 radiographic contrast media and 2 opioid analgesics was tested on a variety of mast cell containing cell suspensions.

Enhancement Factor for Gas Absorption in a Finite Liquid Layer. Part 2: First- and Second-Order Reactions in a Liquid in Plug Flow

Gas absorption accompanied by an irreversible chemical reaction of first-order or second-order in a liquid layer of finite thickness in plug flow has been investigated. The analytical solution to the enhancement factor has been derived for the case of a first-order reaction, and the exact solution to the enhancement factor has been obtained via numerical simulation for the case of a second-order reaction. The enhancement factor in both cases is presented as a function of the Fourier number and tends to deviate from the prediction of the existing enhancement factor expressions based on the penetration theory at Fourier numbers above 0.1 due to the absence of a well-mixed bulk region in the liquid layer. Approximate enhancement factor expressions that describe the analytical and exact solutions with an accuracy of 5?% and 9?%, respectively, have been proposed.

Export of O-specific lipopolysaccharide

The O antigen is the most surface-exposed component of the lipopolysaccharide (LPS) molecule and its biogenesis involves several complex mechanisms not completely well understood. All of these mechanisms involve biochemical reactions that occur on the cytoplasmic side of the plasma membrane as well as several different translocation pathways that deliver the nascent O antigens in a glycolipid form to the periplasmic side of the plasma membrane. This article discusses our current understanding of the mechanisms operating in the biogenesis of the O-specific LPS.

Ubiquitous Nature of Multimode Vibrational Resonances in Positron-Molecule Annihilation

Positron annihilation on many molecules occurs via positron capture into vibrational Feshbach resonances, with annihilation rates often further enhanced by energy transfer to vibrational excitations weakly coupled to the positron continuum. Data presented here uncover another scenario in which the positron couples directly to a quasicontinuum of multimode vibrational states. A model that assumes excitation and escape from a statistically complete ensemble of multimode vibrations is presented that reproduces key features of the data.

Orally bioavailable small molecule drug protects memory in Alzheimer's disease models

Oligomers of beta-amyloid (Aß) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aß-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aß monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aß1-42. Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aß1-42 and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aß and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment. © 2013 Elsevier Inc.

Minimizing side reactions in chemoenzymatic dynamic kinetic resolution: organometallic and material strategies

Chemoenzymatic dynamic kinetic resolution (DKR) of rac-1-phenyl ethanol into R-1-phenylethanol acetate was investigated with emphasis on the minimization of side reactions. The organometallic hydrogen transfer (racemization) catalyst was varied, and this was observed to alter the rate and extent of oxidation of the alcohol to form ketone side products. The performance of highly active catalyst [(pentamethylcyclopentadienyl) IrCl2(1-benzyl,3-methyl-imidazol-2-ylidene)] was found to depend on the batch of lipase B used. The interaction between the bio- and chemo-catalysts was reduced by employing physical entrapment of the enzyme in silica using a sol-gel process. The nature of the gelation method was found to be important, with an alkaline method preferred, as an acidic method was found to initiate a further side reaction, the acid catalyzed dehydration of the secondary alcohol. The acidic gel was found to be a heterogeneous solid acid.

Up-regulation of the endothelial cell adhesion molecule intercellular adhesion molecule-1 (ICAM-1) by autoantibodies in autoimmune vasculitis

Autoimmune vasculitis is characterized by the presence of autoantibodies, particularly anti-neutrophil cytoplasmic antibodies (ANCA) and anti-nuclear antibodies (ANA), in patient sera. These autoantibodies have an incompletely understood role in development of vascular injury. The expression or up-regulation of cell adhesion molecules is an early phase in the development of an inflammatory vascular lesion. Autoantibody-positive sera from patients with vasculitis were assessed for their ability to modulate adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). Autoantibody-positive serum samples from 11 out of 21 patients with primary vasculitis produced substantial up-regulation of ICAM-1 on HUVEC. Autoantibody-negative samples did not produce adhesion molecule up-regulation. Up-regulation of adhesion molecules on HUVEC was observed with samples positive for ANA, a phenomenon not previously reported. Preincubation of the sera with purified antigens recognized by ANCA failed to block this activation. In addition, MoAbs to ANCA antigens were ineffective at inducing ICAM-1 up-regulation, suggesting that activation is independent of the molecular specificity of the antibody. This capacity of ANCA- and ANA-positive sera to up-regulate adhesion molecules on endothelial cells may be a factor in the vessel wall inflammation seen in ANCA-associated vasculitis.

Up-regulation of the granulocyte adhesion molecule Mac-1 by autoantibodies in autoimmune vasculitis

The characteristic finding of autoantibodies in patients with vasculitis has raised the possibility that these antibodies play a role in the pathogenesis of the disease. The expression of adhesion molecules (AM) on leucocytes and endothelial cells is believed to be integral to the development of vasculitis. We therefore investigated the effect of sera, positive for anti-neutrophil cytoplasmic antibodies (ANCA) or anti-nuclear antibodies (ANA) from patients with vasculitis, on granulocyte expression of the adhesion molecule Mac-1 (CD11b). Autoantibody-positive sera from 15 out of 35 patients with vasculitis stimulated an up-regulation of Mac-1 on granulocytes. In most cases this effect was reproduced by the autoantibody-positive purified IgG fraction. Autoantibody-negative samples did not stimulate AM up-regulation. Of interest, preincubation of sera with purified antigens did not inhibit AM up-regulation by the autoantibody samples. Blocking the Fc receptors on granulocytes did result in a decrease of Mac-1 up-regulation, but this trend was not statistically significant. These results suggest that both ANCA and ANA have the capacity to up-regulate granulocyte AM expression, and that while Fc interaction with granulocyte Fc receptors is important, it is not the only mechanism whereby such autoantibodies activate cells.

First report of the use of a saxitoxin-protein conjugate to develop a DNA aptamer to a small molecule toxin

Saxitoxin (STX) is a low molecular weight neurotoxin mainly produced by certain marine dinoflagellates that, along with its family of similarly related paralytic shellfish toxins, may cause the potentially fatal intoxication known as paralytic shellfish poisoning. Illness and fatality rates are low due to the effective monitoring programs that determine when toxins exceed the established regulatory action level and effectuate shellfish harvesting closures accordingly. Such monitoring programs rely on the ability to rapidly screen large volumes of samples. Many of the screening assays currently available employ antibodies or live animals. This research focused on developing an analytical recognition element that would eliminate the challenges associated with the limited availability of antibodies and the use of animals. Here we report the discovery of a DNA aptamer that targets STX. Concentration-dependent and selective binding of the aptamer to STX was determined using a surface plasmon resonance sensor. Not only does this work represent the first reported aptamer to STX, but also the first aptamer to any marine biotoxin. A novel strategy of using a toxin-protein conjugate for DNA aptamer selection was successfully implemented to overcome the challenges associated with aptamer selection to small molecules. Taking advantage of such an approach could lead to increased diversity and accessibility of aptamers to low molecular weight toxins, which could then be incorporated as analytical recognition elements in diagnostic assays for foodborne toxin detection. The selected STX aptamer sequence is provided here, making it available to any investigator for use in assay development for the detection of STX.

Selective Hydrogenation of alpha,beta-Unsaturated Aldehydes and Ketones using Novel Manganese Oxide and Platinum Supported on Manganese Oxide Octahedral Molecular Sieves as Catalysts

The selective hydrogenation of ,-unsaturated aldehydes and ketones has been studied using ketoisophorone and cinnamaldehyde as model substrates using manganese oxide octahedral molecular sieve (OMS-2) based catalysts. For the first time, OMS-2 has been shown to be an efficient and selective hydrogenation catalyst. High selectivities for either the CC or CO double bond at approximate to 100% conversion were achieved by using OMS-2 and platinum supported on OMS-2 catalysts. Density functional theory (DFT) calculations showed that the dissociation of H2 on OMS-2 was water assisted and occurred on the surface Mn of OMS-2(001) that had been modified by an adsorbed H2O molecule. The theoretically calculated activation barrier was in good agreement with the experimentally determined value for the hydrogenation reactions, indicating that H2 dissociation on OMS-2 is likely to be the rate-determining step. A significant increase in the rate of reaction was observed in the presence of Pt as a result of the enhancement of H2 dissociative adsorption and subsequent reaction on the Pt or spillover of the hydrogen to the OMS-2 support. The relative adsorption strengths of ketoisophorone and cinnamaldehyde on the OMS-2 support compared with the Pt were found to determine the product selectivity.