The effect of the proton pump inhibitor pantoprazole on the biology of Campylobacter jejuni

Campylobacter is a major cause of acute bacterial gastroenteritis worldwide, with the highest number of infections being attributed to Campylobacter jejuni. C. jejuni is a Gram negative, spiral, motile bacterium that belongs to the campylobacterales order and is related to both Helicobacter spp. and Wolinella sp.. It has long been established that proton pump inhibitors (PPIs) and other benzimidazole derivatives display anti-Helicobacter activity in vitro. PPIs have in the past been shown to affect Helicobacter pylori growth, survival, motility, morphology, adhesion/invasion potential and susceptibility to conventional antibiotics. PPIs are highly effective drugs that are well tolerated, safe for prolonged daily use and are therefore in high demand. Both the PPIs omeprazole and lansoprazole featured in the top ten drugs prescribed in England in 2014. In 2014 Campylobacter was also the most commonly diagnosed gastrointestinal infection in Scotland, in England and Wales and also in Europe. It has previously been generally accepted that patients who are being treated with PPIs are more susceptible to enteric infections such as Campylobacter than people not taking PPIs. The effect of PPI exposure on H. pylori has been investigated rigorously in the past. A single previous study has hinted that PPIs may also be capable of affecting the related organism C. jejuni,but investigations have been extremely limited in comparison to those investigating the effect of PPIs on H. pylori. This study has investigated the in vitro effects of direct contact with PPIs on the biology ofC. jejuni. Exposure to the PPI pantoprazole was found to affect C. jejuni growth/survival, motility, morphology, biofilm formation, invasion potential and susceptibility to some conventional antibiotics. Microarray studies showed that the cmeA and Cj0561c genes were significantly up-regulated in response to pantoprazole exposure and a CmeABC deficient mutant was found to be significantly more susceptible to killing by pantoprazole than was the parent strain. Proteomic analysis indicated that the oxidative stress response of C. jejuni was induced following exposure to sub-lethal concentrations of pantoprazole. C. jejuni gene expression was assessed using qRT-PCR and the genes encoding for thiol peroxidase and GroEL co-chaperonin (both involved in the C. jejuni oxidative stress response) were found to be around four times higher in response to exposure to sub-lethal concentrations of pantoprazole. Experiments using the oxidative stress inhibitors thiourea (a hydroxyl radical quencher) and bipyridyl (a ferrous iron chelator) showed that killing by pantoprazole was not mediated by hydroxyl radical production.

LHC main dipole magnet circuits: sustaining near-nominal beam energies

Crossing the Franco-Swiss border, the Large Hadron Collider (LHC), designed to collide 7 TeV proton beams, is the world's largest and most powerful particle accelerator the operation of which was originally intended to commence in 2008. Unfortunately, due to an interconnect discontinuity in one of the main dipole circuit's 13 kA superconducting busbars, a catastrophic quench event occurred during initial magnet training, causing significant physical system damage. Furthermore, investigation into the cause found that such discontinuities were not only present in the circuit in question, but throughout the entire LHC. This prevented further magnet training and ultimately resulted in the maximum sustainable beam energy being limited to approximately half that of the design nominal, 3.5-4 TeV, for the first three years of operation (Run 1, 2009-2012) and a major consolidation campaign being scheduled for the first long shutdown (LS 1, 2012-2014). Throughout Run 1, a series of studies attempted to predict the amount of post-installation training quenches still required to qualify each circuit to nominal-energy current levels. With predictions in excess of 80 quenches (each having a recovery time of 8-12+ hours) just to achieve 6.5 TeV and close to 1000 quenches for 7 TeV, it was decided that for Run 2, all systems be at least qualified for 6.5 TeV operation. However, even with all interconnect discontinuities scheduled to be repaired during LS 1, numerous other concerns regarding circuit stability arose. In particular, observations of an erratic behaviour of magnet bypass diodes and the degradation of other potentially weak busbar sections, as well as observations of seemingly random millisecond spikes in beam losses, known as unidentified falling object (UFO) events, which, if persist at 6.5 TeV, may eventually deposit sufficient energy to quench adjacent magnets. In light of the above, the thesis hypothesis states that, even with the observed issues, the LHC main dipole circuits can safely support and sustain near-nominal proton beam energies of at least 6.5 TeV. Research into minimising the risk of magnet training led to the development and implementation of a new qualification method, capable of providing conclusive evidence that all aspects of all circuits, other than the magnets and their internal joints, can safely withstand a quench event at near-nominal current levels, allowing for magnet training to be carried out both systematically and without risk. This method has become known as the Copper Stabiliser Continuity Measurement (CSCM). Results were a success, with all circuits eventually being subject to a full current decay from 6.5 TeV equivalent current levels, with no measurable damage occurring. Research into UFO events led to the development of a numerical model capable of simulating typical UFO events, reproducing entire Run 1 measured event data sets and extrapolating to 6.5 TeV, predicting the likelihood of UFO-induced magnet quenches. Results provided interesting insights into the involved phenomena as well as confirming the possibility of UFO-induced magnet quenches. The model was also capable of predicting that such events, if left unaccounted for, are likely to be commonplace or not, resulting in significant long-term issues for 6.5+ TeV operation. Addressing the thesis hypothesis, the following written works detail the development and results of all CSCM qualification tests and subsequent magnet training as well as the development and simulation results of both 4 TeV and 6.5 TeV UFO event modelling. The thesis concludes, post-LS 1, with the LHC successfully sustaining 6.5 TeV proton beams, but with UFO events, as predicted, resulting in otherwise uninitiated magnet quenches and being at the forefront of system availability issues.