Use of Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry To Resolve Complex Clinical Cases of Patients with Recurrent Bacteremias

Matrix-assisted laser desorption–ionization time of flight mass spectrometry (MALDI-TOF MS) is a rapid and accurate method of identifying microorganisms. Throughout Europe, it is already in routine use but has not yet been widely implemented in the United States, pending FDA approval. Here, we describe two medically complex patients at a large tertiary-care academic medical center with recurring bacteremias caused by distinct but related species. Bacterial identifications were initially obtained using the Vitek-2 system with the GPI card for Enterococcus and the API system for staphylococci. Initial results misled clinicians as to the source and proper management of these patients. Retrospective investigation with MALDI-TOF MS clarified the diagnosis by identifying a single microorganism as the pathogen in each case. To our knowledge, this is one of the first reports in the United States demonstrating the use of MALDI-TOF MS to facilitate the clinical diagnosis in patients with recurrent bacteremias of unclear source.     

Thrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow’s triad

Clinical Rheumatology - The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits...     

Effect of surface modification of polymer beads on the mechanical properties of acrylic bone cement

The effect of surface modification of polymer filler on the static mechanical properties of acrylic bone cement was studied. The surface of polymer beads was modified with carboxylic and amino groups by photochemical reaction with azide compounds. Monomer modifiers (maleic anhydride, methacrylic acid and p-aminostyrene) are attached to the functionalized surface of polymer beads. Functional allyl groups, which are capable of the graft polymerisation reaction, are attached to the surface via photochemical reaction with N-(2-nitro-4-azidophenyl)-N-(-propen) amine. This approach to bone cement provides the additional covalent bonds between the polymer beads and the inter-bead matrix. The static mechanical properties of bone cements containing modified polymer beads were investigated and compared with the static mechanical properties of unmodified cements. The absolute values of compressive strength for the modified and unmodified cements were found to be similar. An increase in flexural strength for the modified cements (dry and after water storage) was observed. The structure of the surface functional groups affects the methyl methacrylate grafting resulting in a higher value of flexural strength for the maleic anhydride- and p-aminostyrene-modified cements. The scanning electron microscopy examination of the fracture surface of the cement samples showed an improvement of the adhesion between the beads and the matrix after modification.     

Association of the endotoxin antagonist E5564 with high-density lipoproteins in vitro: dependence on low-density and triglyceride-rich lipoprotein concentrations

The objective of this study was to determine the distribution profile of the novel endotoxin antagonist E5564 in plasma obtained from fasted human subjects with various lipid concentrations. Radiolabeled E5564 at 1 microM was incubated in fasted plasma from seven human subjects with various total cholesterol (TC) and triglyceride (TG) concentrations for 0.5 to 6 h at 37 degrees C. Following these incubations, plasma samples were separated into their lipoprotein and lipoprotein-deficient fractions by ultracentrifugation and were assayed for E5564 radioactivity. TC, TG, and protein concentrations in each fraction were determined by enzymatic assays. Lipoprotein surface charge within control and phosphatidylinositol-treated plasma and E5564's influence on cholesteryl ester transfer protein (CETP) transfer activity were also determined. We observed that the majority of E5564 was recovered in the high-density lipoprotein (HDL) fraction. We further observed that incubation in plasma with increased levels of TG-rich lipoprotein (TRL) lipid (TC and TG) concentrations resulted in a significant increase in the percentage of E5564 recovered in the TRL fraction. In further experiments, E5564 was preincubated in human TRL. Then, these mixtures were incubated in hypolipidemic human plasma for 0.5 and 6 h at 37 degrees C. Preincubation of E5564 in purified TRL prior to incubation in human plasma resulted in a significant decrease in the percentage of drug recovered in the HDL fraction and an increase in the percentage of drug recovered in the TRL and low-density lipoprotein fractions. These findings suggest that the majority of the drug binds to HDLs. Preincubation of E5564 in TRL prior to incubation in normolipidemic plasma significantly decreased the percentage of drug recovered in the HDL fraction. Modifications to the lipoprotein negative charge did not alter the E5564 concentration in the HDL fraction. In addition, E5564 does not influence CETP-mediated transfer activity. Information from these studies could be used to help identify the possible components of lipoproteins which influence the interaction of E5564 with specific lipoprotein particles.     

Mechanisms to medicines: elucidating neural and molecular substrates of fear extinction to identify novel treatments for anxiety disorders

The burden of anxiety disorders is growing, but the efficacy of available anxiolytic treatments remains inadequate. Cognitive behavioural therapy for anxiety disorders focuses on identifying and modifying maladaptive patterns of thinking and behaving, and has a testable analogue in rodents in the form of fear extinction. A large preclinical literature has amassed in recent years describing the neural and molecular basis of fear extinction in rodents. In this review, we discuss how this work is being harnessed to foster translational research on anxiety disorders and facilitate the search for new anxiolytic treatments. We begin by summarizing the anatomical and functional connectivity of a medial prefrontal cortex (mPFC)–amygdala circuit that subserves fear extinction, including new insights from optogenetics. We then cover some of the approaches that have been taken to model impaired fear extinction and associated impairments with mPFC–amygdala dysfunction. The principal goal of the review is to evaluate evidence that various neurotransmitter and neuromodulator systems mediate fear extinction by modulating the mPFC–amygdala circuitry. To that end, we describe studies that have tested how fear extinction is impaired or facilitated by pharmacological manipulations of dopamine, noradrenaline, 5-HT, GABA, glutamate, neuropeptides, endocannabinoids and various other systems, which either directly target the mPFC–amygdala circuit, or produce behavioural effects that are coincident with functional changes in the circuit. We conclude that there are good grounds to be optimistic that the progress in defining the molecular substrates of mPFC–amygdala circuit function can be effectively leveraged to identify plausible candidates for extinction-promoting therapies for anxiety disorders.

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This article is part of a themed section on Animal Models in Psychiatry Research. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-20