Studies of Established Forms of Therapy for Peptic Ulcer on the Development and Growth of Colorectal Cancer: The Influence of Previous Peptic Ulcer Surgery and Omeprazole

Colorectal cancer and peptic ulcer are two of the most commonly encountered diseases in present day medical practice. The work which is reported in this thesis links these two very different diseases, by investigation of the effects of various forms of treatment for one, on the the incidence and behaviour of the other, both in a deleterious and potentially beneficial fashion to the patient. Many reports have suggested that patients who have previously undergone definitive surgery for peptic ulcer are left with the legacy of an increased propensity for developing malignant disease approximately 15 to 20 years later. Gastric cancer has regularly been identified as being one such cancer. To a much lesser extent, colorectal cancer has also been reported as occurring with undue frequency in a number of patient series studied. With few exceptions, the majority of patients studied have previously undergone partial gastric resection as opposed to vagotomy. The latter procedure, although reducing gastric acid output to a similar degree as partial gastrectomy, differs markedly from it by virtue of the chronic elevation of circulating gastrin levels, secreted from the non-resected stomach, which occurs post-operatively. This may be an important factor in the development of colorectal cancer, as a significant body of evidence suggests that gastrin is trophic for a proportion of such neoplasms. There may therefore be implications for the prolonged use of the latest pharmaceutical agents used against acid-peptic disorders, namely the proton-pump inhibitors of which omeprazole is the original. Similar to vagotomy, these drugs induce a chronic elevation of circulating gastrin, secondary to the reduction in acid output. In view of this association, one of the main purposes of the work which follows was to study the cancer incidence, in particular that of colorectal cancer, in a group of patients who had undergone surgery for peptic ulcer disease, the majority of whom had vagotomy as opposed to antrectomy. Somewhat conversely, the remainder of the work in this thesis concentrates on investigating a possible inhibitory action of omeprazole on colorectal tumour growth, despite the chronic hypergastrinaemia which it produces. This is in response to two recent reports which suggest that the drug may have such an effect on these tumours, under experimental conditions. Hence, it seems appropriate to open this account with a brief overview of the diseases under scrutiny; namely colorectal cancer and peptic ulcer; and to continue by explaining the rationale behind both surgical and medical treatment for the latter. This should give the reader a clear understanding of the pathophysiological changes that occur in response to such treatment, and why they may have potentially deleterious effects, or otherwise, elsewhere in the gastrointestinal tract. In the latter part of the introductory chapter, the evidence, both for and against the phenomena under investigation, will be reviewed, and this will illustrate the stimulus to the work carried out for this thesis

Safety of guselkumab in hepatitis B virus infection

Reactivation of hepatitis B virus (HBV) following the use of TNF antagonists has been reported and is a contraindication to use of these medications. Although the risk of reactivation of HBV during use of ustekinumab and secukinumab is low in patients with only HBV core antibody positivity, the risk is substantial in patients with chronic HBV infection. Less information is available regarding the use of pure IL-23 antagonists. Herein we discuss the successful treatment with guselkumab of a patient with HBV core antibody positivity, without evidence of HBV reactivation or other liver complications

Lateral entorhinal cortex lesions impair odor-context associative memory in male rats

This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) [grant number BB/M010996/1].Lateral entorhinal cortex (LEC) has been hypothesized to process nonspatial, item information that is combined with spatial information from medial entorhinal cortex to form episodic memories within the hippocampus. Recent studies, however, have demonstrated that LEC has a role in integrating features of episodic memory prior to the hippocampus. While the precise role of LEC is still unclear, anatomical studies show that LEC is ideally placed to be a hub integrating multisensory information. The current study tests whether the role of LEC in integrating information extends to long-term multimodal item-context associations. In Experiment 1, male rats were trained on a context-dependent odor discrimination task, where two different contexts served as the cue to the correct odor. Rats were pretrained on the task and then received either bilateral excitotoxic LEC or sham lesions. Following surgery, rats were tested on the previously learned odor-context associations. Control rats showed good memory for the previously learned association but rats with LEC lesions showed significantly impaired performance relative to both their own presurgery performance and to control rats. Experiment 2 went on to test whether impairments in Experiment 1 were the result of LEC lesions impairing either odor or context memory retention alone. Male rats were trained on simple odor and context discrimination tasks that did not require integration of features to solve. Following surgery, both LEC and control rats showed good memory for previously learned odors and contexts. These data show that LEC is critical for long-term odor-context associative memory.Publisher PDFPeer reviewe

Improving Student Attitudes about Science by Integrating Research into the Introductory Chemistry Laboratory: Interdisciplinary Drinking Water Analysis

The integration of student research into a general chemistry laboratory and an environmental geology course has been evaluated for its effectiveness to improve (i) student attitudes about science and chemistry, (ii) student understanding of the nature of experimental science and the scientific method, and (iii) student perceptions of the application of science and the interdisciplinary nature of science. Students in introductory science courses frequently devote all or most of their time and effort to learning basic laboratory techniques by following predefined procedures that have intentionally predictable outcomes. Though this longstanding model of laboratory structure is an important means of effectively preparing students for future chemical study, it often neglects items i−iii. Students were guided through a research experience by an interdisciplinary team of faculty so that students could begin the research and bring it to an appropriate conclusion, including formal presentations, within a single semester. Evaluation of this instructional strategy indicated that students believed they were doing work similar to a research scientist, that they appreciated this opportunity to do research, that it increased how much they like science in general, and that they were more likely to consider majoring in chemistry. The advanced instrumentation, personal relevance of the research, and collaborations (within and outside the department) contributed significantly to the overall success of the project

Telomere dysfunction accurately predicts clinical outcome in chronic lymphocytic leukaemia, even in patients with early stage disease

© 2014 John Wiley & Sons Ltd. Defining the prognosis of individual cancer sufferers remains a significant clinical challenge. Here we assessed the ability of high-resolution single telomere length analysis (STELA), combined with an experimentally derived definition of telomere dysfunction, to predict the clinical outcome of patients with chronic lymphocytic leukaemia (CLL). We defined the upper telomere length threshold at which telomere fusions occur and then used the mean of the telomere 'fusogenic' range as a prognostic tool. Patients with telomeres within the fusogenic range had a significantly shorter overall survival (P  <  0·0001; Hazard ratio [HR] = 13·2, 95% confidence interval [CI]  = 11·6-106·4) and this was preserved in early-stage disease patients (P  <  0·0001, HR=19·3, 95% CI = 17·8-802·5). Indeed, our assay allowed the accurate stratification of Binet stage A patients into those with indolent disease (91% survival at 10 years) and those with poor prognosis (13% survival at 10 years). Furthermore, patients with telomeres above the fusogenic mean showed superior prognosis regardless of their IGHV mutation status or cytogenetic risk group. In keeping with this finding, telomere dysfunction was the dominant variable in multivariate analysis. Taken together, this study provides compelling evidence for the use of high-resolution telomere length analysis coupled with a definition of telomere dysfunction in the prognostic assessment of CLL

Exploring the implementation of Discharge Medicines Review referrals by hospital pharmacy professionals: A qualitative study using the consolidated framework for implementation research

Background The Discharge Medicines Review (DMR) is a community pharmacy service in Wales that aims to reduce medicines-related harm after care transitions, including hospital discharge. To undertake a DMR, the Community Pharmacist must receive a patient's discharge medicines information, either electronically, by fax or presented by the patient. Although the DMR has evidenced benefits for improving patient safety, its evaluation showed inconsistent uptake, which Community Pharmacists partially attributed to hospitals not providing the necessary information. Objective Aiming to develop recommendations to improve hospital engagement to DMR referrals, this study explores hospital pharmacy professionals' views of the service. Methods Qualitative focus groups, using hermeneutic phenomenology, were conducted in 16 hospitals across Wales, using a quota sampling method to include 61 Pharmacists and 31 Pharmacy Technicians. To understand the suboptimal engagement to DMR referrals, framework analysis was undertaken using the Consolidated Framework for Implementation Research (CFIR). Results The data were mapped onto all five CFIR domains, each containing barriers and facilitators to engagement with DMR referrals and suggestions for improvement. Only one hospital had successfully implemented DMR referrals, with many participants lacking any knowledge of the service or how to refer to it. Specific barriers included a clear absence of processes to implement referrals and engage hospital pharmacy professionals. A considerable barrier was many participants' perceptions that Community Pharmacist roles were less clinically orientated and patient-centred than their own, viewing them almost as a different profession. Participants believed that local champions for DMR referrals could promote engagement and integrate them into the workflow of hospital pharmacy professionals. Further recommendations to improve engagement was staff training for DMRs and regular feedback of its value. Conclusion Policymakers may use the findings and recommendations from this study to promote hospital pharmacy staff engagement to similar community pharmacy services like the Discharge Medicines Service in England

Compact corrugated feedhorns with high Gaussian coupling efficiency and -60 dB sidelobes

We demonstrate that very high performance, extremely compact, scalar corrugated feedhorns can be designed and constructed by optimizing the excitation and phasing of the HE11, HE12 and HE13 modes near the throat of the horn whilst limiting excitation of higher order modes. We present the design and measurement of two families of dual-profiled horn, both with a directivity of 20 dBi that couple with very high efficiency to a fundamental Gaussian mode. The first was optimized for sidelobe performance and features sidelobes approaching -60 dB for a horn length of only 15.6λ. The second was designed to minimize horn length and achieves sidelobe levels below -35 dB for a horn which is only 4.8λ long. The horns exhibit excellent coupling to the fundamental free-space Gaussian mode, with LG00 power coupling of 99.92% and 99.75% respectively. We demonstrate excellent agreement between simulation and experiment at 94 GHz and simulate the performance over a 20% bandwidth. High performance compact scalar horns are of interest because they reduce manufacturing risk at high frequencies, and reduce size and weight at lower frequencies, which can be important in horn arrays and space applications, where horn arrays often have serious weight and size restrictions.PostprintPeer reviewe