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Search Results: 1 - 10 of 204446 matches for " Philip N Newsome "
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Impaired gluconeogenesis in a porcine model of paracetamol induced acute liver failure
Konstantinos J Dabos, Henry R Whalen, Philip N Newsome, John A Parkinson, Neil C Henderson, Ian H Sadler, Peter C Hayes, John N Plevris
World Journal of Gastroenterology , 2011,
Abstract: AIM: To investigate glucose homeostasis and in particular gluconeogenesis in a large animal model of acute liver failure (ALF).METHODS: Six pigs with paracetamol induced ALF under general anaesthesia were studied over 25 h. Plasma samples were withdrawn every five hours from a central vein. Three animals were used as controls and were maintained under anaesthesia only. Using 1H NMR spectroscopy we identified most gluconeogenic amino acids along with lactate and pyruvate in the animal plasma samples.RESULTS: No significant changes were observed in the concentrations of the amino acids studied in the animals maintained under anaesthesia only. If we look at the ALF animals, we observed a statistically significant rise of lactate (P < 0.003) and pyruvate (P < 0.018) at the end of the experiments. We also observed statistically significant rises in the concentrations of alanine (P < 0.002), glycine (P < 0.005), threonine (P < 0.048), tyrosine (P < 0.000), phenylalanine (P < 0.000) and isoleucine (P < 0.01). Valine levels decreased significantly (P < 0.05).CONCLUSION: Our pig model of ALF is characterized by an altered gluconeogenetic capacity, an impaired tricarboxylic acid (TCA) cycle and a glycolytic state.
Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure
Philip N Newsome, Neil C Henderson, Leonard J Nelson, Costas Dabos, Celine Filippi, Chris Bellamy, Forbes Howie, Richard E Clutton, Tim King, Alistair Lee, Peter C Hayes, John N Plevris
BMC Gastroenterology , 2010, DOI: 10.1186/1471-230x-10-34
Abstract: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased.Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n = 4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8 +/- 5.9 vs 59 +/- 2.0 mmHg), increased cardiac output (7.26 +/- 1.86 vs 3.30 +/- 0.40 l/min) and decreased systemic vascular resistance (8.48 +/- 2.75 vs 16.2 +/- 1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636 +/- 95 vs 301 +/- 26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome.Liver damage was confirmed by deterioration in pH (7.23 +/- 0.05 vs 7.45 +/- 0.02) and prothrombin time (36 +/- 2 vs 8.9 +/- 0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5 +/- 210 vs 42 +/- 8.14) coincided with a marked reduction in serum albumin (11.5 +/- 1.71 vs 25 +/- 1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2 +/- 36.5 vs 131.6 +/- 9.33 μmol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06.We have developed a reproducible large animal model of acetaminophen-i
A Switch in Hepatic Cortisol Metabolism across the Spectrum of Non Alcoholic Fatty Liver Disease
Adeeba Ahmed, Elizabeth Rabbitt, Theresa Brady, Claire Brown, Peter Guest, Iwona J. Bujalska, Craig Doig, Philip N. Newsome, Stefan Hubscher, Elwyn Elias, David H. Adams, Jeremy W. Tomlinson, Paul M. Stewart
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0029531
Abstract: Context Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH) and cirrhosis. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F) from inactive cortisone (E) (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1), or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR). Objective and Methods In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. Results In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. Conclusion Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may serve to limit hepatic inflammation.
Can Monkeys Choose Optimally When Faced with Noisy Stimuli and Unequal Rewards?
Samuel Feng,Philip Holmes ,Alan Rorie,William T. Newsome
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000284
Abstract: We review the leaky competing accumulator model for two-alternative forced-choice decisions with cued responses, and propose extensions to account for the influence of unequal rewards. Assuming that stimulus information is integrated until the cue to respond arrives and that firing rates of stimulus-selective neurons remain well within physiological bounds, the model reduces to an Ornstein-Uhlenbeck (OU) process that yields explicit expressions for the psychometric function that describes accuracy. From these we compute strategies that optimize the rewards expected over blocks of trials administered with mixed difficulty and reward contingencies. The psychometric function is characterized by two parameters: its midpoint slope, which quantifies a subject's ability to extract signal from noise, and its shift, which measures the bias applied to account for unequal rewards. We fit these to data from two monkeys performing the moving dots task with mixed coherences and reward schedules. We find that their behaviors averaged over multiple sessions are close to optimal, with shifts erring in the direction of smaller penalties. We propose two methods for biasing the OU process to produce such shifts.
Epidemiology of osteoporosis and fractures in ankylosing spondylitis
Philip N Sambrook
Arthritis Research & Therapy , 2012, DOI: 10.1186/ar3724
Abstract: Using the WHO criteria (T score < -2.5), the prevalence of osteoporosis determined by BMD is about 29% in the spine and 12% in the hip in patients with ankylosing spondylitis, which compares with 2% and 1% respectively for controls. Although BMD is generally lower in patients with early disease, with progressive disease, the spine site becomes much less reliable due to the presence of syndesmophytes and periosteal new bone formation. In advanced cases, DXA becomes less reliable but using QCT, bone loss can be shown to continue within the vertebra and hips as well as an increase in cortical BMD and width.The epidemiology of fractures in ankylosing spondylitis remains unclear although vertebral fractures have been most studied. The risk of clinical vertebral fractures is significantly increased (OR approximately 7.7 95% CI 4.3-12.6) and the cumulative incidence of clinical vertebral fractures is higher in men (OR 10.7 versus 4.2 in women) and increased especially during the first 5 years of the disease. The prevalence and incidence of non-vertebral fractures has been less well studied but in most reports appears to be about the same as in the control population.Managing skeletal complications in anklosing spondylitis should include DXA of the spine and hip early in the disease. In more advanced disease, spinal DXA is not a useful predictor of fracture. In these circumstances, QCT should be considered. If a vertebral fracture is suspected, spinal imaging is required in order to avoid delays in diagnosis and therapy.
Knowledge Building: Reinventing Education for the Knowledge Age
Donald N. Philip
International Education Studies , 2011, DOI: 10.5539/ies.v4n4p118
Abstract: This paper examines the Knowledge Age and how economic factors are causing educators to rethink and reinvent education. Two key factors in education in the Knowledge Age will be education for an economy of innovation, and the increasing virtualization of education. We present knowledge building pedagogy as a model for education in the Knowledge Age and discuss Knowledge Forum, online knowledge building environment designed to facilitate and support the knowledge building process. Built into Knowledge Forum is a suit of online tools that track the interactions that students have with Knowledge Forum. We focus on the social network tool that allows us to examine communication patterns among the students when working online. Using the data obtained, we examine the growth and development of online community formation during the first week of class for a group of na ve users in a third-year university class. Examining the note reading and response networks, we see that the note reading network develops more rapidly than the responding network, and that it is more symmetric than the responding network. However, by mid-term, a highly connected network has developed for both note-reading and responding.
The Replication and Excess of Disciplinary Power in Sekigun and Aum Shinrikyo - A Foucaultian Approach
Philip N Eate
New Voices : A Journal for Emerging Scholars of Japanese Studies in Australia and New Zealand , 2008,
Abstract: This article aims to explain why both the left wing extremist group Sekigun (Red Army) and the new religious sect Aum Shinrikyo (The Supreme Truth of Aum) adopted violent and deadly forms of disciplinary power in their pursuit of an idealistic society.The approach in this article differs from the existing literature in that it is mainly concerned with why both groups failed to provide a more preferable alternative to the existing state structure and finally internalised their violence, torturing their own members.Foucaultian theory will be utilised in order to analyse the role that hierarchy and hierarchical surveillance played in re-enforcing the harsh discipline and training methods used by both groups. In this approach this article will show that despite the efforts of both Sekigun and Aum Shinrikyo to create the antithesis to everything they rejected within Japanese society they each paradoxically reproduced and magnified within their own social organisations the least desirable societal traits of elitism, exclusivity and conformity using the most extreme disciplinary measures to do so.
High-throughput phenotyping of multicellular organisms: finding the link between genotype and phenotype
Rosangela Sozzani, Philip N Benfey
Genome Biology , 2011, DOI: 10.1186/gb-2011-12-3-219
Abstract: The availability of complete genomic sequences of many model organisms has made it possible to perform highly informative genome-wide functional analyses. For multicellular organisms (including the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, the plants Arabidopsis thaliana and rice, as well as mouse), phenotypic analysis of genetic mutations is still one of the most effective ways to explore the function of a gene. Collections of strains with mutations in nearly every gene are now available, making it possible to analyze the phenotypes of a large number of independent strains. However, conventional analytic approaches, such as high-magnification microscopy at the single-cell level, require manual manipulation of samples and screening by eye, thus limiting throughput and presenting bottlenecks to large-scale genetic studies in multicellular organisms. Therefore, development of high-throughput methods, including automation in phenotyping and screening, is a strategy that is now coming to fruition [1]. Systematic large-scale phenotyping efforts have begun to generate information on a previously unattainable scale. For example, it was recently shown that even a highly dynamic process such as the division of human cells can be studied on a genome-wide scale by live imaging [2].Cultured cells have also proved amenable to high-throughput phenotyping [2]. Although more challenging, the study of living organisms can provide insights into biological pathways, regulatory networks and/or cellular activity and behavior not obtainable from cultured cells [3-6]. Large-scale acquisition of phenotypic data can then predict important biological outputs, such as the roles of individual genes in development. Thus, high-throughput phenotyping approaches (that is, phenomics) can encompass a broad range of model systems and techniques aimed at understanding the link between genotype and phenotype.A good example of the evolution of high-throughput phenotyping is
Are Lay People Good at Recognising the Symptoms of Schizophrenia?
Philip Erritty, Taeko N. Wydell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052913
Abstract: Aim The aim of this study was to explore the general public’s perception of schizophrenia symptoms and the need to seek-help for symptoms. The recognition (or ‘labelling’) of schizophrenia symptoms, help-seeking behaviours and public awareness of schizophrenia have been suggested as potentially important factors relating to untreated psychosis. Method Participants were asked to rate to what extent they believe vignettes describing classic symptoms (positive and negative) of schizophrenia indicate mental illness. They were also asked if the individuals depicted in the vignettes required help or treatment and asked to suggest what kind of help or treatment. Results Only three positive symptoms (i.e., Hallucinatory behaviour, Unusual thought content and Suspiciousness) of schizophrenia were reasonably well perceived (above 70%) as indicating mental illness more than the other positive or negative symptoms. Even when the participants recognised that the symptoms indicated mental illness, not everyone recommended professional help. Conclusion There may be a need to improve public awareness of schizophrenia and psychosis symptoms, particularly regarding an awareness of the importance of early intervention for psychosis.
Euclidean formulation of relativistic quantum mechanics
W. N. Polyzou,Philip Kopp
Physics , 2009,
Abstract: We discuss preliminary work on a formulation of relativistic quantum mechanics that uses reflection-positive Euclidean Green functions or their generating functionals as phenomenological input. We discuss the construction of a Poincare invariant S-matrix from matrix element of exp(- \beta H).
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