The Effects and Mechanism of Action of Cimetidine on Inducible Nitric Oxide Synthase Using an Equine Soft-Tissue Inflammation Model.

Cytochrome P-450 (CYP) and inducible nitric oxide synthase (iNOS) are similar heme containing enzymes. Cimetidine (CIM) is an H2 antagonist, and since CIM inhibits CYP, it may also bind to the heme-iron of NOS and reduce NO generation. Six horses each had three tissue chambers inserted subcutaneously on either side of the neck for Trial 1. Trial 2 also used 6 female Thoroughbred horses implanted with at least two tissue chambers as in Trial 1. Blood and tissue chamber fluid (TCF) were sampled at -24, 0, 4, 8, 12 h and at 1, 2, 3, 5, and 7 days after carrageenan instillation for Trial 1 a similar schedule was used for Trial 2. Tissue chamber fluid (TCF) interleukin (IL)-1 concentrations were increased following NaCl inflamed (NaCl-I), CIM, or aminoguanidine (AG) treatment when compared to non-inflamed chamber TCF. For IL-6, NaCl-I and CIM were significantly increased when compared to NaCl non-inflamed (-N). There was no significant difference between the area under the curve (AUC) of IL-1 or IL-6 in NaCl-I TCF vs. CIM or AG TCF. Cimetidine significantly decreased NO3 - AUCs in plasma. Aminoguanidine and CIM decreased NO3 - AUCs in TCF in Trials 1 and 2. These results indicate that CIM had an effect on some inflammatory indices in this model. Surprising is the inhibition of NO3- formation by CIM. This could be the result of direct inhibition of NOS, direct inhibition of CYP, and/or an interaction at H2 receptors that have a role in the regulation of NOS. For CIM, classical Type II spectra, similar to those previously reported, were obtained at concentrations ≥0.1 mm in both rat and equine hepatic microsome preparations. Both hexobarbital and AG produced a Type I difference spectra in rat and equine hepatic microsome preparations. The interaction of CIM with a leukocyte preparation resulted in atypical spectra, but provided evidence for interaction with a chromophore in TCF. Cimetidine also did not affect the conversion of NO to NO3- catalyzed by hemoglobin. Western blot analysis, however, failed to identify NOS in the leukocyte preparation

Global assessment of exposure to faecal contamination through drinking water based on a systematic review

Objectives: To estimate exposure to faecal contamination through drinking water as indicated by levels of Escherichia coli (E. coli) or thermotolerant coliform (TTC) in water sources. Methods: We estimated coverage of different types of drinking water source based on household surveys and censuses using multilevel modelling. Coverage data were combined with water quality studies that assessed E. coli or TTC including those identified by a systematic review (n = 345). Predictive models for the presence and level of contamination of drinking water sources were developed using random effects logistic regression and selected covariates. We assessed sensitivity of estimated exposure to study quality, indicator bacteria and separately considered nationally randomised surveys. Results: We estimate that 1.8 billion people globally use a source of drinking water which suffers from faecal contamination, of these 1.1 billion drink water that is of at least 'moderate' risk (>10 E. coli or TTC per 100 ml). Data from nationally randomised studies suggest that 10% of improved sources may be 'high' risk, containing at least 100 E. coli or TTC per 100 ml. Drinking water is found to be more often contaminated in rural areas (41%, CI: 31%-51%) than in urban areas (12%, CI: 8-18%), and contamination is most prevalent in Africa (53%, CI: 42%-63%) and South-East Asia (35%, CI: 24%-45%). Estimates were not sensitive to the exclusion of low quality studies or restriction to studies reporting E. coli. Conclusions: Microbial contamination is widespread and affects all water source types, including piped supplies. Global burden of disease estimates may have substantially understated the disease burden associated with inadequate water services

Cherenkov luminescence measurements with digital silicon photomultipliers: a feasibility study.

BackgroundA feasibility study was done to assess the capability of digital silicon photomultipliers to measure the Cherenkov luminescence emitted by a β source. Cherenkov luminescence imaging (CLI) is possible with a charge coupled device (CCD) based technology, but a stand-alone technique for quantitative activity measurements based on Cherenkov luminescence has not yet been developed. Silicon photomultipliers (SiPMs) are photon counting devices with a fast impulse response and can potentially be used to quantify β-emitting radiotracer distributions by CLI.MethodsIn this study, a Philips digital photon counting (PDPC) silicon photomultiplier detector was evaluated for measuring Cherenkov luminescence. The PDPC detector is a matrix of avalanche photodiodes, which were read one at a time in a dark count map (DCM) measurement mode (much like a CCD). This reduces the device active area but allows the information from a single avalanche photodiode to be preserved, which is not possible with analog SiPMs. An algorithm to reject the noisiest photodiodes and to correct the measured count rate for the dark current was developed.ResultsThe results show that, in DCM mode and at (10-13) °C, the PDPC has a dynamic response to different levels of Cherenkov luminescence emitted by a β source and transmitted through an opaque medium. This suggests the potential for this approach to provide quantitative activity measurements. Interestingly, the potential use of the PDPC in DCM mode for direct imaging of Cherenkov luminescence, as a opposed to a scalar measurement device, was also apparent.ConclusionsWe showed that a PDPC tile in DCM mode is able to detect and image a β source through its Cherenkov radiation emission. The detector's dynamic response to different levels of radiation suggests its potential quantitative capabilities, and the DCM mode allows imaging with a better spatial resolution than the conventional event-triggered mode. Finally, the same acquisition procedure and data processing could be employed also for other low light levels applications, such as bioluminescence

Low-dose antibiotics: current status and outlook for the future

Antimicrobial therapy is a key factor in our success against pathogens poised to ravage at risk or infected individuals. However, we are currently at a watershed point as we face a growing crisis of antibiotic resistance among diverse pathogens. One area of intense interest is the impact of the application of antibiotics for uses other than the treatment of patients and the association with such utilization with emerging drug resistance. This Research Topic “Low- dose antibiotics: current status and outlook for the future” in Frontiers in Microbiology: Antimicrobials, Resistance and Chemotherapy details various aspects of the wide ranging effects of antimicrobial therapy from areas such as the regulation of host responses to modulation of bacterial virulence factors to acquisition of antibiotic resistance genes

An output coupler for a W-band high power wideband gyro-amplifier

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) U.K. under Research Grant EP/K029746/1, and Science and Technology Facilities Council (STFC) U.K. under Research Grants ST/K006673/1 & ST/K006703/1, ST/N002326/1 & ST/N002318/1.An output coupler for a W-band high power wideband gyro-amplifier has been designed, manufactured and experimentally measured. It consists of a high performance sin2-parallel corrugated horn integrated with a broadband multi-layer window. The major design requirements are that the horn/window combination must have an input return loss lower than -30 dB over a 10 GHz bandwidth, provide a high quality output beam pattern, and operate under ultra-high vacuum conditions. The coupler converts a circular wave guide TE11 mode into the free space Laguerre Gaussian LG00 mode over the frequency band of 90–100 GHz with a measured return loss of between -30 and -40 dB and a simulated Gaussian coupling efficiency of over 99% at 94 GHz.PostprintPeer reviewe

High-sensitivity Gd3+-Gd3+ EPR distance measurements that eliminate artefacts seen at short distances

We would like to acknowledge EPSRC (EP/R)13705/1) for current funding on the HiPER project, and the Wellcome Trust for a multi-user equipment grant (099149/Z/12/Z) for upgrades on the Q-band system. We thank the Royal Society for an International Exchanges Grant and The Weizmann-UK Joint Research Program for allowing bilateral travel and research between the University of St Andrews and the Weizmann Institute of Science. JEL thanks the Royal Society for a University Research Fellowship. MJT thanks EPSRC for a CM-CDT studentship (EP/LO15110/1). MQ and AG thank the Deutsche Forschungsgemeinschaft (DFG) for funding within SPP 1601 (GO555/6-2).Gadolinium complexes are attracting increasing attention as spin labels for EPR dipolar distance measurements in biomolecules and particularly for in-cell measurements. It has been shown that flip-flop transitions within the central transition of the high spin Gd3+ ion can introduce artefacts in dipolar distance measurements, particularly when measuring distances less than 3–4 nm. Previous work has shown some reduction of these artefacts through increasing the frequency separation between the two frequencies required for the Double Electron-Electron Resonance (DEER) experiment. Here we use a high power (1 kW), wideband, non-resonant, system operating at 94 GHz to evaluate DEER measurement protocols using two rigid Gd(III)-rulers, consisting of two [GdIII(PyMTA)] complexes, with separations of 2.1 nm and 6.0 nm, respectively. We show that by avoiding the |−1/2⟩ → |1/2⟩ central transition completely, and placing both the pump and the observer pulses on either side of the central transition, we can now observe apparently artefact-free spectra and narrow distance distributions, even for a Gd-Gd distance of 2.1 nm. Importantly we still maintain excellent signal-to-noise ratio and relatively high modulation depths. These results have implications for in-cell EPR measurements at naturally occurring biomolecule concentrations.Publisher PDFPeer reviewe

Synthesis of nuclear waste simulants by reaction precipitation: formation of caesium phosphomolybdate, zirconium molybdate and morphology modification with citratomolybdate complex

Caesium phosphomolybdate (CsPMoO·xHO) and zirconium molybdate ([ZrMoO(OH)]·2HO) solids are known to precipitate out from highly active liquors (HAL) during reprocessing of spent nuclear fuel. Here, a new synthesis for these simulants is reported; with the initial step producing spherical ceasium phosphomolybdate particles, which can then be converted into cubic Zirconium molybdate. Additionally, the addition of citric acid prior to the formation of the zirconium salt is investigated. In this case, a citratomolybdate complex is generated, leading to the synthesis of elongated cuboidal zirconium citratomolybdate ([ZrMoO(OH)]·2HO·[(MoO)O(cit)]). A key focus of this study is to explore the optimisation of reaction conditions to create a controlled environment for the particles to form with high conversion rates and with desired shape properties. Elemental and structural characterisation of the particles at various points during the synthesis, as well as post-synthesis, was undertaken to provide further insights. Ultimately, it is of importance to determine the mechanism of how these simulants are formed within the components in HAL. Establishing the influence of particle properties on HAL behaviour is key for current processing, post operational clean out (POCO) and life-time assessment of the nuclear waste facilities

The Upper Respiratory Tract as a Microbial Source for Pulmonary Infections in Cystic Fibrosis. Parallels from Island Biogeography

A continuously mixed series of microbial communities inhabits various points of the respiratory tract, with community composition determined by distance from colonization sources, colonization rates, and extinction rates. Ecology and evolution theory developed in the context of biogeography is relevant to clinical microbiology and could reframe the interpretation of recent studies comparing communities from lung explant samples, sputum samples, and oropharyngeal swabs. We propose an island biogeography model of the microbial communities inhabiting different niches in human airways. Island biogeography as applied to communities separated by time and space is a useful parallel for exploring microbial colonization of healthy and diseased lungs, with the potential to inform our understanding of microbial community dynamics and the relevance of microbes detected in different sample types. In this perspective, we focus on the intermixed microbial communities inhabiting different regions of the airways of patients with cystic fibrosis

Telecommunication wavelength GaAsBi light emitting diodes

GaAsBi light emitting diodes containing ∼6% Bi are grown on GaAs substrates. Good room-temperature electroluminescence spectra are obtained at current densities as low as 8 Acm − 2. Measurements of the integrated emitted luminescence suggest that there is a continuum of localised Bi states extending up to 75 meV into the bandgap, which is in good agreement with previous photoluminescence studies. X-ray diffraction analysis shows that strain relaxation has probably occurred in the thicker samples grown in this study

An Experimental Feasibility Study on Robotic Endonasal Telesurgery

Novel robots have recently been developed specifically for endonasal surgery. They can deliver several thin, tentacle-like surgical instruments through a single nostril. Among the many potential advantages of such a robotic system is the prospect of telesurgery over long distances