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The Cambridge companion to Frege
\"Gottlob Frege (1848-1925) was unquestionably one of the most important philosophers of all time. He trained as a mathematician, and his work in philosophy started as an attempt to provide an explanation of the truths of arithmetic, but in the course of this attempt he not only founded modern logic but also had to address fundamental questions in the philosophy of language and philosophical logic. Frege is generally seen (along with Russell and Wittgenstein) as one of the fathers of the analytic method, which dominated philosophy in English-speaking countries for most of the twentieth century. His work is studied today not just for its historical importance but also because many of his ideas are still seen as relevant to current debates in the philosophies of logic, language, mathematics and the mind. The Cambridge Companion to Frege provides a route into this lively area of research\"-- Provided by publisher.
Book
Evidence-Based and Emerging Diet Recommendations for Small Bowel Disorders
Diet plays a key role in the manifestation and severity of gastrointestinal symptoms, with increasing research interest on the role of diet in small bowel disorders. There are predominantly 3 small bowel conditions that have potential dietary interventions. Self-reported nonceliac gluten/wheat sensitivity is prevalent. Although gluten is believed to be a potential trigger for symptoms, other components of wheat may also be triggers, including fructans, alpha-amylase trypsin inhibitors, and wheat germ agglutinins. The diagnosis can be challenging, given the lack of validated biomarkers. A gluten-free diet that excludes the abovementioned triggers is the cornerstone of treatment; however, unlike celiac disease, there is uncertainty about the level of adherence or whether the gluten-free diet is a lifelong intervention. Several primary gastrointestinal disorders are associated with an increase in inflammatory cells including eosinophils. Diet seems to be an important driver of disease pathogenesis in eosinophilic gastroenteritis, with elimination and elemental diets showing promise in management, with further robust trials required. Small intestinal bacterial overgrowth is an example of microbial dysbiosis, with renewed interest in diet being postulated to cause an adaptive change of the microbes colonizing the small intestine. However, the diagnosis of small intestinal bacterial overgrowth is limited by a lack of sensitive and specific tests, with significant knowledge gaps in relation to therapeutic measures to manage and cure small intestinal bacterial overgrowth. Currently, antimicrobials are the established management option. There have been significant clinical advances in dietary interventions related to the small bowel, but this area is currently a novel and advancing field for both patients and clinicians.
Journal Article
Type 2 and type 17 effector cells are increased in the duodenal mucosa but not peripheral blood of patients with functional dyspepsia
Functional dyspepsia is characterised by chronic symptoms of post-prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cells have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific phenotype was associated with FD.
This study aimed to characterise T cell populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology.
We identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry using a surface marker antibody panel. We also analysed T cell populations in peripheral blood from 37 controls and 61 patients. Where available, we examined the number of duodenal eosinophils in patients and controls.
There was a shift in the duodenal T helper cell balance in FD patients compared to controls. For example, patients had increased duodenal mucosal Th2 populations in the effector (13.03 ± 16.11, 19.84 ± 15.51,
=0.038), central memory (23.75 ± 18.97, 37.52 ± 17.51,
=0.007) and effector memory (9.80±10.50 vs 20.53±14.15,
=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75,
=0.03) and effector memory (11.95±8.42 vs 18.44±15.63,
=0.027) subsets. Peripheral T cell populations were unchanged between FD and control.
Our findings identify an association between lymphocyte populations and FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.
Journal Article
Wheat Intolerance and Chronic Gastrointestinal Symptoms in an Australian Population-based Study: Association Between Wheat Sensitivity, Celiac Disease and Functional Gastrointestinal Disorders
OBJECTIVESWheat avoidance in the absence of celiac disease (CD) is common but occurrence of concurrent functional gastrointestinal disorders (FGIDs) in this group is uncertain. The aims of this study were to determine the prevalence of self-reported wheat or gluten sensitivity and doctor diagnosed CD in an Australian population, define the associated gastrointestinal (GI) symptoms and FGIDs, and determine the relationship between self-reported wheat sensitivity, demographic and medical factors.MethodsA total of 3542 people randomly selected from the Australian population returned a mail survey which contained questions on wheat avoidance, GI symptoms, demographic, medical, and lifestyle factors. We defined self-reported wheat sensitivity as people who reported gastrointestinal symptoms on ingestion of wheat based foods, but did not suffer from celiac disease, inflammatory bowel disease or colorectal cancer. Functional dyspepsia (FD) and irritable bowel syndrome (IBS) were diagnosed by Rome III criteria. CD status was self-reported.ResultsThe prevalence of self-reported wheat sensitivity in this cohort was 14.9% (95% CI 13.7–16.2). The prevalence of CD was 1.2% (95%CI 0.8–1.6). Doctor diagnosed CD was significantly associated with a diagnosis of FD (OR 3.35, 95%CI 1.72–6.52) and IBS (OR 2.28, 95%CI 1.08–4.81). Those with self-reported wheat sensitivity were more likely to report multiple abdominal symptoms (of the 18 assessed) than those without (3.9 symptoms with self-reported wheat sensitivity vs. 1.6 without, p = 0.0001). In a multivariate analysis, self-reported wheat sensitivity was independently associated with IBS (OR 3.55, 95%CI 2.71–4.65) and FD (1.48, 95%CI 1.13–1.94).ConclusionsSelf-reported wheat sensitivity is common, with a prevalence of 14.9% in this cohort. There is a strong association between both celiac disease and self-reported wheat sensitivity, and chronic gastrointestinal symptoms, as well as a diagnosis of FD and IBS.
Journal Article
Proton pump inhibitors and suppression of duodenal eosinophilia in functional dyspepsia
Correspondence to Dr Michael D E Potter, Faculty of Health and Medicine, University of Newcastle, Callaghan NSW 2305, Australia; michael.potter@newcastle.edu.au We read with interest the study by Molina-Infante et al 1 regarding proton pump inhibitor (PPI) responsive oesophageal eosinophilia. The authors emphasise that the benefit of PPI therapy may be secondary to anti-inflammatory effects (blocking of STAT 6) rather than antisecretory properties, which raises the question whether PPI therapy may be beneficial in other eosinophilic disease of the gastrointestinal tract. FD has been linked with subtle duodenal eosinophilia in several studies, with a mean eosinophil count of 49±22 (mm2±SD) in the second part of the duodenum (D2) significantly associated with the diagnosis.3 PPIs are efficacious in the treatment of FD, and based on several randomised controlled trials, is recommended as first-line therapy in those who are Helicobacter pylori negative, or in those whom symptoms persist following H. pylori eradication.4 PPIs are known to have a number of novel effects that cannot be explained simply by a reduction in acid secretion, including suppression of the T helper 2-cytokine-stimulated expression of the eosinophil chemoattractant eotaxin.5 We hypothesised that PPIs may exert a therapeutic effect in FD via suppression of duodenal eosinophils and that a reduction in both symptom scores and duodenal eosinophils would be observed in patients with FD on PPI therapy.
Journal Article
Wheat Sensitivity and Functional Dyspepsia: A Pilot, Double-Blind, Randomized, Placebo-Controlled Dietary Crossover Trial with Novel Challenge Protocol
Introduction: Functional dyspepsia (FD), characterised by symptoms of epigastric pain or early satiety and post prandial distress, has been associated with duodenal eosinophilia, raising the possibility that it is driven by an environmental allergen. Non-coeliac gluten or wheat sensitivity (NCG/WS) has also been associated with both dyspeptic symptoms and duodenal eosinophilia, suggesting an overlap between these two conditions. The aim of this study was to evaluate the role of wheat (specifically gluten and fructans) in symptom reduction in participants with FD in a pilot randomized double-blind, placebo controlled, dietary crossover trial. Methods: Patients with Rome III criteria FD were recruited from a single tertiary centre in Newcastle, Australia. All were individually counselled on a diet low in both gluten and fermentable oligo-, di-, mono-saccharides, and polyols (FODMAPs) by a clinical dietitian, which was followed for four weeks (elimination diet phase). Those who had a ≥30% response to the run-in diet, as measured by the Nepean Dyspepsia Index, were then re-challenged with ‘muesli’ bars containing either gluten, fructan, or placebo in randomised order. Those with symptoms which significantly reduced during the elimination diet, but reliably reappeared (a mean change in overall dyspeptic symptoms of ≥30%) with gluten or fructan re-challenge were deemed to have wheat induced FD. Results: Eleven participants were enrolled in the study (75% female, mean age 43 years). Of the initial cohort, nine participants completed the elimination diet phase of whom four qualified for the rechallenge phase. The gluten-free, low FODMAP diet led to an overall (albeit non-significant) improvement in symptoms of functional dyspepsia in the diet elimination phase (mean NDI symptom score 71.2 vs. 47.1, p = 0.087). A specific food trigger could not be reliably demonstrated. Conclusions: Although a gluten-free, low-FODMAP diet led to a modest overall reduction in symptoms in this cohort of FD patients, a specific trigger could not be identified. The modified Salerno criteria for NCG/WS identification trialled in this dietary rechallenge protocol was fit-for-purpose. However, larger trials are required to determine whether particular components of wheat induce symptoms in functional dyspepsia.
Journal Article
A Serological Diagnosis of Coeliac Disease Is Associated with Osteoporosis in Older Australian Adults
Previously thought to be mainly a disorder of childhood and early adult life, coeliac disease (CeD) is increasingly diagnosed in older adults. This may be important given the association between CeD and osteoporosis. The primary aim of this study was to determine the seroprevalence of undiagnosed CeD (‘at-risk serology’) in an older Australian community and relate this to a diagnosis of osteoporosis and fractures during a follow-up period of 12 years. We included participants from the Hunter Community Study (2004–2007) aged 55–85, who had anti-tissue transglutaminase (tTG) titres, human leukocyte antigen (HLA) genotypes, and bone mineral density measurements at baseline. Follow-up data included subsequent diagnosis of CeD and fractures using hospital information. ‘At-risk’ serology was defined as both tTG and HLA positivity. Complete results were obtained from 2122 patients. The prevalence of ‘at-risk’ serology was 5%. At baseline, 3.4% fulfilled criteria for a diagnosis of osteoporosis. During a mean of 9.7 years of follow-up, 7.4% of the cohort suffered at least one fracture and 0.7% were subsequently diagnosed with CeD. At-risk serology was significantly associated with osteoporosis in a multivariate model (odds ratio 2.83, 95% confidence interval 1.29–6.22); there was insufficient power to look at the outcome of fractures. The results of this study demonstrate that at-risk CeD serology was significantly associated with concurrent osteoporosis but not future fractures. Most individuals with a serological diagnosis of CeD were not diagnosed with CeD during the follow-up period according to medical records. Coeliac disease likely remains under-diagnosed.
Journal Article