A New SiF–Dipropargyl Glycerol Scaffold as a Versatile Prosthetic Group to Design Dimeric Radioligands: Synthesis of the [18F]BMPPSiF Tracer to Image Serotonin Receptors

A novel SiX–dipropargyl glycerol scaffold (X: H, F, or ¹⁸F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre‐ or post‐labeling with fluorine‐18. Rapid conjugation with the prosthetic group takes place in microwave‐assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX–dipropargyl glycerol derivatized radioligand, [¹⁸F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5‐HT_1A receptor‐rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein–flexible ligand) of BMPPSiF and known antagonists (WAY‐100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5‐HT_1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: ?6.766 as compared with all three antagonists on the monomeric model. Multimeric induced‐fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of ?8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX–dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids.     

Gene therapy for articular cartilage repair

Articular cartilage serves as the gliding surface of joints. It is susceptible to damage from trauma and from degenerative diseases. Restoration of damaged articular cartilage may be achievable through the use of cell-regulatory molecules that augment the reparative activities of the cells, inhibit the cells' degradative activities, or both. A variety of such molecules have been identified. These include insulin-like growth factor I, fibroblast growth factor 2, bone morphogenetic proteins 2, 4, and 7, and interleukin-1 receptor antagonist. It is now possible to transfer the genes encoding such molecules into articular cartilage and synovial lining cells. Although preliminary, data from in-vitro and in-vivo studies suggest that gene therapy can deliver such potentially therapeutic agents to protect existing cartilage and to build new cartilage.     

Contaminant blubber burdens in Atlantic bottlenose dolphins (Tursiops truncatus) from two southeastern US estuarine areas: Concentrations and patterns of PCBs, pesticides, PBDEs, PFCs, and PAHs

Polychlorinated biphenyls (PCBs), chlorinated pesticides (i.e., dichlorodiphenyltrichloroethane (DDT) and its metabolites, chlordanes (CHLs), dieldrin, hexachlorobenzene (HCB), and mirex), polybrominated diphenyl ethers (PBDEs), perfluorinated chemicals (PFCs), and polyaromatic hydrocarbons (PAHs) were measured in blubber biopsy samples collected from 139 wild bottlenose dolphins (Tursiops truncatus) during 2003-2005 in Charleston (CHS), SC and the Indian River Lagoon (IRL), FL. Dolphins accumulated a similar suite of contaminants with ∑ PCB dominating (CHS 64%, IRL 72%), followed by ∑ DDT (CHS 20%, IRL 17%), ∑ CHLs (CHS 7%; IRL 7%), ∑ PBDE (CHS 4%, IRL 2%), PAH at 2%, and dieldrin, PFCs and mirex each 1% or less. Together ∑ PCB and ∑ DDT concentrations contributed ∼ 87% of the total POCs measured in blubber of adult males. ∑ PCBs in adult male dolphins exceed the established PCB threshold of 17 mg/kg by a 5-fold order of magnitude with a 15-fold increase for many animals; 88% of the dolphins exceed this threshold. For male dolphins, CHS (93,980 ng/g lipid) had a higher ∑ PCBs geomean compared to the IRL (79,752 ng/g lipid) although not statistically different. In adult males, the PBDE geometric mean concentration was significantly higher in CHS (5920 ng/g lipid) than the IRL (1487 ng/g). Blubber ∑ PFCs concentrations were significantly higher in CHS dolphins. In addition to differences in concentration of PCB congeners, ∑ PBDE, TEQ, ∑ CHLs, mirex, dieldrin, and the ratios ∑ DDE/∑DDT and trans-nonachlor/cis-nonachlor were the most informative for discriminating contaminant loads in these two dolphin populations. Collectively, the current ∑ PCB, ∑ DDT, and ∑ PBDEs blubber concentrations found in CHS dolphins are among the highest reported values in marine mammals. Both dolphin populations, particularly those in CHS, carry a suite of organic chemicals at or above the level where adverse effects have been reported in wildlife, humans, and laboratory animals warranting further examination of the potential adverse effects of these exposures.     

Characterization of fibre/matrix interfaces in carbon/carbon composites

The present paper proposes an approach to characterizing fibre/matrix (F/M) interface in carbon/carbon (C/C) composites with respect to both modes of loading that may be expected: opening or shearing. Push-out and tensile tests were used. The former tests involve the shearing mode whereas the latter ones involve the opening one. Push-out tests use a diamond indenter to load the fibres. The interface sliding shear stress was obtained from the load-fibre displacement curve. The tensile tests were conducted on specimens having fibres oriented at 90° with respect to loading direction in order to preferentially open the interfaces. Interface opening strength was extracted from the composite tensile stress–strain behaviour. The specimens were examined under load and after ultimate failure by optical microscopy (OM). The mechanical properties of the F/M interfaces were then discussed.     

Distraction and driving: Results from a case–control responsibility study of traffic crash injured drivers interviewed at the emergency room

Background

Use of cellular phones has been shown to be associated with crashes but many external distractions remain to be studied.

Objective

To assess the risk associated with diversion of attention due to unexpected events or secondary tasks at the wheel.

Design

Responsibility case–control study.

Setting

Adult emergency department of the Bordeaux University Hospital (France) from April 2010 to August 2011.

Participants

955 injured drivers presenting as a result of motor vehicle crash.

Main outcome measures

The main outcome variable was responsibility for the crash. Exposures were external distraction, alcohol use, psychotropic medicine use, and sleep deprivation. Potential confounders were sociodemographic and crash characteristics.

Results

Beyond classical risk factor found to be associated with responsibility, results showed that distracting events inside the vehicle (picking up an object), distraction due to driver activity (smoking) and distracting events occurring outside were associated with an increased probability of being at fault. These distraction-related factors accounted for 8% of injurious road crashes.

Limitations

Retrospective responsibility self-assessment.

Conclusions

Diverted attention may carry more risk than expected. Our results are supporting recent research efforts to detect periods of driving vulnerability related to inattention.     

Microelectrode biosensor for real-time measurement of ATP in biological tissue

The purines ATP, ADP, and adenosine are important extracellular signaling agents. Analysis of purinergic signaling has been slowed by lack of direct methods for measurement of purine release in real-time during physiological activity. We have previously reported microelectrode biosensors for adenosine, but similar sensors for ATP have remained elusive. We now describe an ATP biosensor formed by coating a Pt microelectrode with an ultrathin biolayer containing glycerol kinase and glycerol-3-phosphate oxidase. It responds rapidly (10-90% rise time <10 s) and exhibits a linear response to ATP over the physiologically relevant concentrations of 200 nM-50 microM and is very sensitive approximately 250 mA.M(-1).cm(-2). By including phosphocreatine kinase in the biolayer, we can optionally amplify the ATP signal and also make the sensor sensitive to external ADP. We have used our sensors to make the first demonstration that ATP is released from spinal networks in vivo during locomotor activity.     

Development and validation of a near-infrared method for the quantitation of caffeine in intact single tablets

A near-infrared spectroscopic method was developed and validated for determining the caffeine concentration of single and intact tablets in a Finnish pharmaceutical product containing 58.82% (m/m) caffeine.The spectral region of interest contained a total of 474 data points. The second derivative of Savitsky-Golay, a standard normal variate, and mean centering were used as spectral preprocessing options. The feasibility study showed nonuniformity of caffeine repartition within each tablet. Thus, spectra were recorded from both faces of the tablets, and the analysis result for a single tablet was reported as the average of both face determinations. Precision of the method was validated because the relative standard deviations from repeatability and intermediate precision tests were below 0.75% (m/m). Accuracy validation proved that the NIR results were not significantly different (P = 0.09, n = 12) from the results obtained with the reference HPLC method. The limit of quantification for caffeine was 13.7% (m/m) in the tablets. The method was found to be unaffected by NIR source replacement, but the repeatability of the results was affected if the sample holder was not placed in the correct position in the light beam. Routine NIR analysis of caffeine in tablet form was found to be more flexible and much faster than that performed with the HPLC method.     

Thermal Shock Resistance of Ladle Castables

High purity alumina-spinel( A-MA) and alumina-magnesia( A-M) castables are widely used in steel ladles due to their resistance against slag penetration and corrosion. With a calcium magnesium aluminate bond( CMA) excellent slag penetration resistance can be achieved which results in high wear resistance due to reduced structural spalling. This paper investigates the impact of matrix compositions and CMA-binder content of A-MA and A-M castables on thermal shock resistance( TSR). Standardized thermal shock tests have been applied with sample quenching from 950 ℃ down to room temperature. Results show that all castables are significantly damaged after 5 cycles despite their differences in microstructure. However,the mix with 12%CMA gave TSR that is at similar good level as the reference mix with 6% CAC( 70% alumina cement). While a similar strength level was achieved before and after the thermal cycling,the formulation with 12% CMA contains 0. 6% less total Ca O. The A-MA castables perform better on average than the A-M mixes with this test method. Within the group of A-M castables the mix with 18% CMA and 0. 5% SiO_2 gave superior TSR,similar good as castables of the A-MA group. The introduction of CMA in an A-M castable allows reduction of free Mg O and SiO_2-addition. The reduction of SiO_2 has been found beneficial for the TSR. This was also found during a thermal cycling trial at high temperature between 1 100 and 1 500 ℃. Here the A-M mix with18% CMA and 0. 5% SiO_2 performed better than the SiO_2-free A-MA castable.