Dietetics, Nutrition and Biological Sciences
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Item High Titers of Transmissible Spongiform Encephalopathy Infectivity Associated with Extremely Low Levels of PrPSc in Vivo(American Society for Biochemistry and Molecular Biology, 2007-10-08) Barron, Rona; Campbell, Susan L.; King, Declan; Bellon, Anne; Chapman, Karen E.; Williamson, R. Anthony; Manson, Jean C.Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humans and ruminants relies on the detection in post-mortem brain tissue of the protease-resistant form of the host glycoprotein PrP. The presence of this abnormal isoform (PrPSc) in tissues is taken as indicative of the presence of TSE infectivity. Here we demonstrate conclusively that high titers of TSE infectivity can be present in brain tissue of animals that show clinical and vacuolar signs of TSE disease but contain low or undetectable levels of PrPSc. This work questions the correlation between PrPSc level and the titer of infectivity and shows that tissues containing little or no proteinase K-resistant PrP can be infectious and harbor high titers of TSE infectivity. Reliance on protease-resistant PrPSc as a sole measure of infectivity may therefore in some instances significantly underestimate biological properties of diagnostic samples, thereby undermining efforts to contain and eradicate TSEs.Item Host PrP Glycosylation: A Major Factor Determining the Outcome of Prion Infection(Public Library of Science, 2008-04-15) Tuzi, Nadia L.; Cancellotti, Enrico; Baybutt, Herbert; Blackford, Lorraine; Bradford, Barry; Pinston, Chris; Coghill, Anne; Hart, Patricia; Piccardo, Pedro; Barron, Rona; Manson, Jean C.The expression of the prion protein (PrP) is essential for transmissible spongiform encephalopathy (TSE) or prion diseases to occur, but the underlying mechanism of infection remains unresolved. To address the hypothesis that glycosylation of host PrP is a major factor influencing TSE infection, we have inoculated gene-targeted transgenic mice that have restricted N-linked glycosylation of PrP with three TSE strains. We have uniquely demonstrated that mice expressing only unglycosylated PrP can sustain a TSE infection, despite altered cellular location of the host PrP. Moreover we have shown that brain material from mice infected with TSE that have only unglycosylated PrPSc is capable of transmitting infection to wild-type mice, demonstrating that glycosylation of PrP is not essential for establishing infection within a host or for transmitting TSE infectivity to a new host. We have further dissected the requirement of each glycosylation site and have shown that different TSE strains have dramatically different requirements for each of the glycosylation sites of host PrP, and moreover, we have shown that the host PrP has a major role in determining the glycosylation state of de novo generated PrPSc.Item Molecular Model of Prion Transmission to Humans(Centers for Disease Control and Prevention, 2009-12) Jones, Michael; Wight, Darren; Barron, Rona; Jeffrey, Martin; Manson, Jean; Prowse, Christopher; Ironside, James W.; Head, Mark W.To assess interspecies barriers to transmission of transmissible spongiform encephalopathies, we investigated the ability of disease-associated prion proteins (PrPd) to initiate conversion of the human normal cellular form of prion protein of the 3 major PRNP polymorphic variants in vitro. Protein misfolding cyclic amplification showed that conformation of PrPd partly determines host susceptibility.Item Differential protein profiling as a potential multi-marker approach for TSE diagnosis(BMC, 2009-11-27) Barr, Janice B.; Watson, Michael; Head, Mark W.; Ironside, James W.; Harris, Nathan; Hogarth, Caroline; Fraser, Janet R.; Barron, RonaThis "proof of concept" study, examines the use of differential protein expression profiling using surface enhanced laser desorption and ionisationtime of flight mass spectrometry (SELDI-TOF) for the diagnosis of TSE disease. Spectral output from all proteins selectively captured from individual murine brain homogenate samples, are compared as "profiles" in groups of infected and non-infected animals. Differential protein expression between groups is thus highlighted and statistically significant protein "peaks" used to construct a panel of disease specific markers. Studies at both terminal stages of disease and throughout the time course of disease have shown a disease specific protein profile or "disease fingerprint" which could be used to distinguish between groups of TSE infected and uninfected animals at an early time point of disease. Results Our results show many differentially expressed proteins in diseased and control animals, some at early stages of disease. Three proteins identified by SELDI-TOF analysis were verified by immunohistochemistry in brain tissue sections. We demonstrate that by combining the most statistically significant changes in expression, a panel of markers can be constructed that can distinguish between TSE diseased and normal animals. Conclusion Differential protein expression profiling has the potential to be used for the detection of disease in TSE infected animals. Having established that a "training set" of potential markers can be constructed, more work would be required to further test the specificity and sensitivity of the assay in a "testing set". Based on these promising results, further studies are being performed using blood samples from infected sheep to assess the potential use of SELDI-TOF as a pre-mortem blood based diagnostic.Item Phenotypic changes in the lipopolysaccaride of Pseudomonas aeruginosa and E.coli grown in milk-based enteral nutrient solutions(Elsevier, 1999-01) Hodgson, Ian; Stewart, John; Fyfe, LornaPrevious studies have shown enteral nutritional solutions (ENS) contaminated with large numbers of microorganisms from the environment or gastrointestinal (GI) tract of patients have caused respiratory infections, acute and chronic enteritis, and septicemia. The introduction of closed- enteral feeding systems has been used to prevent contaminating organisms from entering enteral feeding systems in large numbers. However, there is some discussion as to whether this has been an effective measure in reducing ENS-related infections because there is anecdotal evidence to suggest that disease processes resulting from enteral feeding are still commonplace in the hospital and home. This is because there is very little information about the growth of microorganisms in ENS and whether growth in ENS may affect the virulence and pathogenicity of microorganisms. This study shows that Escherichia coli and Pseudomonas aeruginosa may grow at 25C from either high or low initial numbers to up to 9.2 log colony-forming units per mL in a range of milk-based ENS. However, these organisms did not grow in the fruit-based ENS. The effect on the lipopolysaccharide (LPS) of culturing E. coli and P. aeruginosa in milk-based ENS as opposed to standard laboratory media was examined using polyacrylamide gel electrophoresis. We found that there were significant qualitative changes in the phenotype of O-polysaccharide side chains of the LPS from these organisms. O-polysaccharide is known to mediate in the complement, antibiotic and bile resistance, and affect adherence. Therefore, changes in the virulence and pathogenicity of these microorganisms when cultured in ENS may be indicated. Thus, the study provides further evidence for reevaluating the microbiologic and immunologic effects of enteral feeding, especially on the microbial flora of the GI tract.Item Nutritional status of elective gastrointestinal surgery patients pre- and post-operatively(Elsevier, 2002-06) Davidson, Isobel; Fettes, Sheila; Richardson, Rosemary A.; Pennington, ChristopherBackground and Aims: Studies have indicated that undernutrition is common on admission to hospital but there is limited data on change in nutritional parameters during the hospital stay. We assessed the nutritional status of elective gastrointestinal surgery patients on admission and documented change in nutritional indices during hospitalisation.Methods: Two hundred patients aged 18-80 years undergoing elective open gastrointestinal surgery were nutritionally assessed on admission and 150 were reassessed on commencement of oral diet post-surgery. Data were collected on height, weight, upper arm anthropometry and hand-grip dynamometry. Results: On admission BMI <20, 20-24.9 and >25, respectively, were found in 9%, 34% and 57% of patients. Post-surgery, 34% of patients experienced a clinically significant weight loss. Males lost significantly more weight (3.7% vs 1.6%, P<0.001) and tended to lose muscle mass while females preferentially lost subcutaneous fat. Conclusions: The incidence of undernutrition on admission appears to be lower than previously reported. However, clinically significant weight loss was common and this study highlighted gender differences in the changes in nutritional parameters experienced by gastrointestinal surgery patients. This differential influence of gender warrants further investigation and may have implications for the nutritional management of such patients.Item The administration of an oral carbohydrate-containing fluid prior to major elective upper-gastrointestinal surgery preserves skeletal muscle mass postoperatively : a randomised clinical trial(Elsevier, 2005-02) Davidson, Isobel; Richardson, Rosemary A.; Yuill, K. A.; Garde, O. J.; Parks, R. W.Aim: Recent evidence suggests that the provision of energy-containing fluids is safe and may impact positively on markers of recovery. The aims of this study were to assess the tolerance of preoperative carbohydrate fluid administration and to determine its effect on postoperative metabolic and clinical responses. Methods: Patients admitted to the Royal Infirmary of Edinburgh for major, elective abdominal surgery were recruited to this double-blind, randomised study and received either a placebo drink or carbohydrate (12.6 g/100 ml) drink (CHOD). Patients consumed 800 ml of their drink on the evening before surgery and 400 ml on the day of surgery 2-3 h before the induction of anaesthesia. Nutritional status was determined using body mass index (BMI) and upper arm anthropometry; all measurements were taken preoperatively, postoperatively and at discharge. Blood glucose and insulin concentrations were also measured preoperatively and on the first post operative day. Length of hospital stay (LOS) and postoperative complications were recorded. Results: Seventy-two patients were recruited and 65 (34 male:31 female) completed this study. Thirty-four patients were randomised to receive the placebo drink (control group) and 31 patients to receive the carbohydrate drink (CHOD group). Groups were well-matched in terms of gender and age. There were no differences between the two groups at baseline for BMI (control: -25.11.7 kg/m2; CHOD -25.21.2 kg/m2), upper arm anthropometry or surgical procedure. At discharge loss of muscle mass (arm muscle circumference) was significantly greater in the control group when compared with the CHOD group (control: -1.10.15 cm; CHOD: -0.50.16 cm; P<0.05). Baseline insulin (control: 20.74.9mU/l; CHOD: 24.66.2mU/l) and glucose (control: 6.01.4 mmol/l; CHOD 5.71.4 mmol/l) were comparable in the two groups and did not differ postoperatively. No complications were recorded as a result of preoperative fluid consumption. Postoperative morbidity occurred in six patients from each group. Median LOS in the control group was 10 days (IQR=6), and 8 days (IQR=4) in the CHOD group. Conclusion: Preoperative consumption of carbohydrate-containing fluids is safe. Provision of a carbohydrate energy source prior to surgery may attenuate depletion of muscle mass after surgery. Further studies are required to determine if this preservation of muscle mass is reflected in improved function and reduced rehabilitation time.Item Nutritional demands in acute and chronic illness(Cambridge University Press, 2003-11) Davidson, Isobel; Richardson, Rosemary A.Common to both acute and chronic disease are disturbances in energy homeostasis, which are evidenced by quantitative and qualitative changes in dietary intake and increased energy expenditure. Negative energy balance results in loss of fat and lean tissue. The management of patients with metabolically-active disease appears to be simple; it would involve the provision of sufficient energy to promote tissue accretion. However, two fundamental issues serve to prevent nutritional demands in disease being met. The determination of appropriate energy requirements relies on predictive formulae. While equations have been developed for critically-ill populations, accurate energy prescribing in the acute setting is uncommon. Only 25-32% of the patients have energy intakes within 10% of their requirements. Clearly, the variation in energy expenditure has led to difficulties in accurately defining the energy needs of the individual. Second, the acute inflammatory response initiated by the host can have profound effects on ingestive behaviour, but this area is poorly understood by practising clinicians. For example, nutritional targets have been set for specific disease states, i.e. pancreatitis 105-147 KJ (25-35 kcal)/kg; chronic liver disease 147-168 kj (35-40 kcl)/kg, but given the alterations in gut physiology that accompany the acute-phase response, targets are unlikely to be met. In cancer cachexia attenuation of the inflammatory response using eicosapentaenoic acid results in improved nutritional intake and status. This strategy poses an attractive proposition in the quest to define nutritional support as a clinically-effective treatment modality in other disorders.Item There's something fishy about omega-3(Nutritiion Society, 2009) McKenzie, JaneTo make things slightly complicated, where the food industry use the term omega-3 or 3 when talking about this particular kind of polyunsaturated fatty acid, the scientists now call them n-3 (n minus 3) - which refers to the location in the molecule of the last double bond. This new term will eventually start replacing omega-3 on food packaging, but for this article we will stick with the familiar name.Item Strategies to improve ingestive behaviour with reference to critical illness(CUP, 2007) Davidson, Isobel; Smith, SaraThe complex interplay between neural and endocrine responses following food intake regulates ingestive behaviour and ultimately determines subsequent energy intake. These processes include cognitive, gastrointestinal-derived and metabolic mechanisms. Such physiological responses to the ingestion of food initiate short- to medium-term inhibition of intake (satiety). However, in clinical states in which systemic inflammation is evident there is a more profound satiety response and a clear absence of motivation to eat that is evident as loss of appetite. These negative influences on energy intake can contribute to poor nutritional status, and consequently poor physical function, and impact on rehabilitation and recovery. Cytokine mediators of the inflammatory response directly influence feeding behaviour at the hypothalamic nuclei and may explain the lack of motivation and desire for food. However, additional detrimental effects on appetite are brought about because of alterations in intermediary metabolism present in inflammation-induced catabolism. This process forms part of the host response to inflammation and may explain symptoms, such as early satiety, frequently reported in many patient groups. In clinical states, and cancer in particular, pharmacological strategies have been employed to ameliorate the inflammatory response in an attempt to improve energy intake. Some success of this approach has been reported following administration of substrates such as EPA. Novel strategies to improve intake through administration of anti-cytokine drugs such as thalidomide may also be of benefit. However, drugs that oppose the actions of neurotransmitter pathways involved in central induction of satiety, such as 5-hydroxytryptamine, have failed to improve intake but appear to enhance enjoyment of food. Such findings indicate that therapeutic nutritional targets can only be achieved where novel pharmacological therapies can be supported by more innovative and integrated dietary management strategies. Many of these strategies remain to be elucidated.