Showing papers by "University of Oxford published in 1995"

Viral dynamics in human immunodeficiency virus type 1 infection

Abstract: The dynamics of HIV-1 replication in vivo are largely unknown yet they are critical to our understanding of disease pathogenesis. Experimental drugs that are potent inhibitors of viral replication can be used to show that the composite lifespan of plasma virus and virus-producing cells is remarkably short (half-life approximately 2 days). Almost complete replacement of wild-type virus in plasma by drug-resistant variants occurs after fourteen days, indicating that HIV-1 viraemia is sustained primarily by a dynamic process involving continuous rounds of de novo virus infection and replication and rapid cell turnover.

The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey

Abstract: Summary BACKGROUND AND OBJECTIVE The original Whlckham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the Incidence and natural history of thyroid disease in this cohort. DESIGN, PATIENTS AND MEASUREMENTS Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, In addition to death certificates, two-thirds had Information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91 % were tested for clinical, biochemical and Immunological evidence of thyroid dysfunction. RESULTS Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean Incidence (with 95% confidence Intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism In women was 0.8/1000 survivors/year (0.5.1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an Increase with age In hypothyroidism but no age relation in hyperthyroidism. The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially. The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors Identified at first survey. The odds ratios (with 95% confidence Intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A loglt model Indicated that Increasing values of serum TSH above 2mU/l at first survey Increased the probability of developing hypothyroidism which was further Increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with Increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism In women. CONCLUSIONS This historical cohort study has provided Incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease Identified twenty years earlier.

A new approach for filtering nonlinear systems

Abstract: In this paper we describe a new recursive linear estimator for filtering systems with nonlinear process and observation models. This method uses a new parameterisation of the mean and covariance which can be transformed directly by the system equations to give predictions of the transformed mean and covariance. We show that this technique is more accurate and far easier to implement than an extended Kalman filter. Specifically, we present empirical results for the application of the new filter to the highly nonlinear kinematics of maneuvering vehicles.

Competition when Consumers have Switching Costs: An Overview with Applications to Industrial Organization, Macroeconomics, and International Trade

Abstract: We survey recent work on competition in markets in which consumers have costs of switching between competing firms' products, even when all firms' products are functionally identical We address issues in macroeconomics and international trade, as well as industrial organization: In a market with switching costs (or 'brand loyalty'), a firm's current market share is an important determinant of its future profitability We examine how the firm's choice between setting a low price to capture market share, and setting a high price to Harvest profits by exploiting its current locked-in customers, is affected by the threat of new entry interest rates, exchange rate expectations, the state of the business cycle, etc We also discuss the causes of switching costs, explain introductory offers and price wars, and examine industry profits, firms' product choices, and implications for multi-product competition

Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons

Abstract: SYNCHRONIZATION of neuronal activity is fundamental in the operation of cortical networks. With respect to an ongoing synchronized oscillation, the precise timing of action potentials is an attractive candidate mechanism for information coding. Networks of inhibitory interneurons have been proposed to have a role in entraining cortical, synchronized 40-Hz activity. Here we demonstrate that individual GABAergic interneurons can effectively phase spontaneous firing and subthreshold oscillations in hippocampal pyramidal cells at 0 frequencies (4-7 Hz). The efficiency of this entrainment is due to interaction of GABAA-receptor-mediated hyperpolarizing synaptic events with intrinsic oscillatory mechanisms tuned to this frequency range in pyramidal cells. Moreover, this GABAergic mechanism is sufficient to synchronize the firing of pyramidal cells. Thus, owing to the divergence of each GABAergic interneuron, more than a thousand pyramidal cells may share a common temporal reference established by an individual interneuron.

Inverse entailment and PROGOL

Abstract: This paper firstly provides a re-appraisal of the development of techniques for inverting deduction, secondly introduces Mode-Directed Inverse Entailment (MDIE) as a generalisation and enhancement of previous approaches and thirdly describes an implementation of MDIE in the Progol system. Progol is implemented in C and available by anonymous ftp. The re-assessment of previous techniques in terms of inverse implication leads to new results for learning from positive data and inverting implication between pairs of clauses.

Comparative analysis by independent contrasts (CAIC): an Apple Macintosh application for analysing comparative data.

Abstract: CAIC is an application for the Apple Macintosh which allows the valid analysis of comparative (multi-species) data sets that include continuous variables. Comparison among species is the most common technique for testing hypotheses of how organisms are adapted to their environments, but standard statistical tests like regression should not be used with species data. Such tests assume independence of data points, but related species often share traits by common descent rather than through independent adaptation. CAIC uses a phylogeny of the species in the data set to partition the variance among species into independent comparisons (technically, linear contrasts), each comparison being made at a different node in the phylogeny. There are two partitioning procedures--one used when all variables are continuous, the other when one variable is discrete. The resulting comparisons can be analysed validly in standard statistical packages to test hypotheses about correlated evolution among traits, to estimate parameters such as allometric exponents, and to compare rates of evolution. Previous versions of the package have already been used widely; this version is simpler to use and works on a wider range of machines. The package and manual are freely available by anonymous ftp or from the authors.

Expression of a Delta homologue in prospective neurons in the chick

Abstract: The product of the Delta gene, acting as ligand, and that of the Notch gene, acting as receptor, are key components in a lateral-inhibition signalling pathway that regulates the detailed patterning of many different tissues in Drosophila. During neurogenesis in particular, neural precursors, by expressing Delta, inhibit neighbouring Notch-expressing cells from becoming committed to a neural fate. Vertebrates are known to have several Notch genes, but their functions are unclear and their ligands hitherto unidentified. Here we identify and describe a chick Delta homologue, C-Delta-1. We show that C-Delta-1 is expressed in prospective neurons during neurogenesis, as new cells are being born and their fates decided. Our data from the chick, combined with parallel evidence from Xenopus, suggest that both the Delta/Notch signalling mechanism and its role in neurogenesis have been conserved in vertebrates.

Developmental biology of the pancreas

Abstract: The pancreas is an organ containing two distinct populations of cells, the exocrine cells that secrete enzymes into the digestive tract, and the endocrine cells that secrete hormones into the bloodstream. It arises from the endoderm as a dorsal and a ventral bud which fuse together to form the single organ. Mammals, birds, reptiles and amphibians have a pancreas with similar histology and mode of development, while in some fish, the islet cells are segregated as Brockmann bodies. Invertebrates do not have a pancreas, but comparable endocrine cells may be found in the gut or the brain. The early pancreatic bud shows uniform expression of the homeobox gene IPF-1 (also known as IDX-1, STF-1 or PDX), which when mutated to inactivity leads to total absence of the organ. The occurrence of heterotopic pancreas in the embryo, and also the metaplasias that can be displayed by a regenerating pancreas in the adult, both suggest that only a few gene products distinguish the pancreatic cell state from that of the surrounding tissues of duodenum, gall bladder and liver. In the developing pancreatic buds, the endocrine cells start to differentiate before the exocrine cells, and co-expression of different hormones by the same cell is often observed at early stages. Although pancreatic endocrine cells produce many gene products also characteristic of neurons, evidence from in vitro cultures and from quailchick grafts shows that they are of endogenous and not of neural crest origin. Observational studies suggest strongly that both endocrine and exocrine cells arise from the same endodermal rudiment. Development of the pancreas in embryonic life requires a trophic stimulus from the associated mesenchyme. In postnatal life, all cell types in the pancreas continue to grow. Destruction of acinar tissue by duct ligation or ethionine treatment is followed by rapid regeneration. Surgical removal of parts of the pancreas is followed by moderate but incomplete regeneration of both acini and islets. Poisoning with alloxan or streptozotocin can lead to permanent depletion of beta cells. Although the cell kinetics of the pancreas are not understood, it seems likely that there is a continuous slow turnover of cells, fed from a stem cells population in the ducts, and that the controls on the production rate of each cell type are local rather than systemic.

The development and validation of a short measure of functioning and well being for individuals with Parkinson's disease.

Abstract: Parkinson's disease is a common degenerative neurological condition. A number of general health status measures exist but these may not address areas salient to specific diseases. We report here the development and validation of a short 39 item health status questionnaire for use in Parkinson's disease. Questionnaire items, generated from in-depth interviews with people with Parkinson's disease, were developed into a 65 item questionnaire. Data from a postal survey using the 65 item questionnaire were statistically analysed to produce a shorter questionnaire with 39 items and eight scales addressing different dimensions of Parkinson's disease. A second postal survey was conducted in order to assess the reliability and validity of the new 39 item questionnaire. The final questionnaire, referred to here as the 39 item Parkinson's Disease Questionnaire (PDQ-39), proved to have satisfactory internal and test-retest reliability, and construct validity in relation to other measures, reported by respondents with Parkinson's disease.

Self-initiated versus externally triggered movements. I. An investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson's disease subjects

Abstract: We investigated the functional anatomy of self-initiated and externally triggered movements. Six patients with Parkinson's disease off medication and six age-matched normals were assessed. All subjects had regional cerebral blood flow (rCBF) measurement with PET and recording of movement-related cortical potentials (MRPs) from frontal (F), fronto-central (FC), central (C) and parietal (P) sites to obtain measures of the Bereitschaftspotential (BP). The tasks were (i) self-initiated extension of the right index finger on average once every 3 s, (ii) externally triggered finger extension with the rate yoked to the self-initiated task, and (iii) rest condition with tones presented at a rate yoked with the self-initiated task. For the self-initiated movements, the amplitude of the early and peak BP were lower in Parkinson's disease relative to normals. For the externally triggered movements, the patients and the normals did not differ on any of the measures of cortical negativity prior to movement. For both groups, the late and peak BP components, but not the early component, had a lower amplitude in the externally triggered than the self-initiated movements. In normals, the left primary sensorimotor cortex, the supplementary motor area bilaterally, anterior cingulate, the lateral premotor cortex bilaterally, the insular cortex bilaterally, the left thalamus and the left putamen, parietal area 40 bilaterally and the right dorsolateral prefrontal cortex (DLPFC) were significantly activated during the self-initiated movements relative to rest. For the normals, greater activation of the right DLPFC during the self-initiated movements was the only area that significantly differentiated them from the externally triggered movements. When Parkinson's disease patients and normals were compared for the self-initiated movements relative to rest, normals showed greater activation of the supplementary motor area and anterior cingulate, left putamen, left insular cortex, right DLPFC and right parietal area 40. When the groups were compared for the externally triggered movements relative to rest, the global pattern of blood flow and rCBF change in the two groups did not differ, confirming the absence of group differences in BPs for the externally triggered movements. During the self-initiated movements, the lower amplitude of the early BP in patients with Parkinson's disease as well as the underactivation of the supplementary motor area relative to normals support the premises that (i) the supplementary motor area contributes to the early BP, and (ii) the deficit is self-initiated movements in Parkinson's disease is due to supplementary motor area underactivation. The DLPFC is activated in situations requiring non-routine decision making as in the self-initiated movements.

Self-Ownership, Freedom and Equality

Abstract: In this book G. A. Cohen examines the libertarian principle of self-ownership, which says that each person belongs to himself and therefore owes no service or product to anyone else. This principle is used to defend capitalist inequality, which is said to reflect each person's freedom to do as he wishes with himself. The author argues that self-ownership cannot deliver the freedom it promises to secure, thereby undermining the idea that lovers of freedom should embrace capitalism and the inequality that comes with it. He goes on to show that the standard Marxist condemnation of exploitation implies an endorsement of self-ownership, since, in the Marxist conception, the employer steals from the worker what should belong to her, because she produced it. Thereby a deeply inegalitarian notion has penetrated what is in aspiration an egalitarian theory. Purging that notion from socialist thought, he argues, enables construction of a more consistent egalitarianism.

Conditional Quantum Dynamics and Logic Gates

Abstract: Quantum logic gates provide fundamental examples of conditional quantum dynamics. They could form the building blocks of general quantum information processing systems which have recently been shown to have many interesting nonclassical properties. We describe a simple quantum logic gate, the quantum controlled-NOT, and analyze some of its applications. We discuss two possible physical realizations of the gate, one based on Ramsey atomic interferometry and the other on the selective driving of optical resonances of two subsystems undergoing a dipole-dipole interaction.

Glycosylation changes of IgG associated with rheumatoid arthritis can activate complement via the mannose-binding protein.

Abstract: The glycosylation of the circulating immunoglobulin-gamma (IgG) antibody molecules changes in rheumatoid arthritis The extent of the changes correlates with the disease severity and reverses in remission We demonstrate here that the alteration in glycosylation associated with rheumatoid arthritis can create a new mode for the interaction of IgG with complement through binding to the collagenous lectin mannose-binding protein (MBP) Rheumatoid arthritis is associated with a marked increases in IgG glycoforms that lack galactose (referred to as G0 glycoforms) in the Fc region of the molecule and that terminate in N-acetyl glucosamine (GlcNAc) We show, using nuclear magnetic resonance (NMR) and X-ray data, that these terminal GlcNAc residues become accessible for MBP binding We further demonstrate that multiple presentation of IgG-G0 glycoforms to MBP results in activation of the complement This suggests that a contribution to the chronic inflammation of the synovial membrane could arise from the localization of the IgG-G0 glycoforms in the affected joint and from resulting activation of complement

A transient three-plasmid expression system for the production of high titer retroviral vectors

Abstract: We have constructed a series of MLV-based retroviral vectors and packaging components expressed from the CMV promoter and carried on plasmids containing SV40 origins of replication. These two features greatly enhanced retroviral gene expression when introduced into cell lines carrying the SV40 large T antigen. The two packaging components, gag-pol and env, were placed on separate plasmids to reduce helper virus formation. Using a highly transfectable human cell line and sodium butyrate to further increase expression of each component, we achieved helper-free viral stocks of approximately 10(7) infectious units/ml by 48 h after transient co-transfection with the three plasmid components. This system can be used both for the generation of high titer retroviral stocks for transduction and for the rapid screening of a large number of MLV gag-pol or env mutants.

Inertial navigation systems for mobile robots

Abstract: A low-cost solid-state inertial navigation system (INS) for mobile robotics applications is described. Error models for the inertial sensors are generated and included in an extended Kalman filter (EKF) for estimating the position and orientation of a moving robot vehicle. Two different solid-state gyroscopes have been evaluated for estimating the orientation of the robot. Performance of the gyroscopes with error models is compared to the performance when the error models are excluded from the system. Similar error models have been developed for each axis of a solid-state triaxial accelerometer and for a conducting-bubble tilt sensor which may also be used as a low-cost accelerometer. An integrated inertial platform consisting of three gyroscopes, a triaxial accelerometer and two tilt sensors is described. >

Meta-cognition and worry: A cognitive model of generalized anxiety disorder.

Abstract: A meta-cognitive classification and analysis of factors contributing to the development of problematic worry is presented. Dimensions of meta-beliefs, meta-worry, cognitive consciousness, and strategies can be distinguished. A cognitive model of Generalized Anxiety Disorder is advanced based on this framework in which GAD results from an interaction between the motivated use of worry as a coping strategy, negative appraisal of worry, and worry control attempts. These factors result from combinations of dysfunctional meta-beliefs and contribute to subjectively diminished cognitive control. The model presents new implications for a cognitive therapy of GAD, and these are illustrated with a single case treatment study.

A composite estimate of primate phylogeny

Abstract: This paper presents an estimate of the phylogeny of all 203 species of primate. The composite tree is derived by applying a parsimony algorithm to over a hundred previous estimates, and is well resolved, containing 160 nodes. The ages of over half the clades in the tree have been estimated from information in the literature. Bootstrapping has been used to indicate the degree of certainty associated with each clade. The tree will be a useful framework for comparative biologists and shows which areas of primate phylogeny are still only sketchily known.

Primary neurogenesis in Xenopus embryos regulated by a homologue of the Drosophila neurogenic gene Delta.

Abstract: X-Delta-1, a Xenopus homologue of the Drosophila Delta gene, is expressed in the early embryonic nervous system in scattered cells that appear to be the prospective primary neurons. Ectopic X-Delta-1 activity inhibits production of primary neurons and interference with endogenous X-Delta-1 activity results in overproduction of primary neurons. These results indicate that the X-Delta-1 protein mediates lateral inhibition delivered by prospective neurons to adjacent cells, and that commitment to a neural fate in vertebrates is regulated by Delta-Notch signalling as in Drosophila.

Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B.

Abstract: The crystal structures of a cysteine-215-->serine mutant of protein tyrosine phosphatase 1B complexed with high-affinity peptide substrates corresponding to an autophosphorylation site of the epidermal growth factor receptor were determined. Peptide binding to the protein phosphatase was accompanied by a conformational change of a surface loop that created a phosphotyrosine recognition pocket and induced a catalytically competent form of the enzyme. The phosphotyrosine side chain is buried within the period and anchors the peptide substrate to its binding site. Hydrogen bonds between peptide main-chain atoms and the protein contribute to binding affinity, and specific interactions of acidic residues of the peptide with basic residues on the surface of the enzyme confer sequence specificity.

Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria.

Abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common enzymopathy of humans, affects over 400 million people. The geographical correlation of its distribution with the historical endemicity of malaria suggests that this disorder has risen in frequency through natural selection by malaria. However, attempts to confirm that G6PD deficiency is protective in case-control studies of malaria have yielded conflicting results. Hence, for this X-linked disorder, it is unclear whether both male hemizygotes and female heterozygotes are protected or, as frequently suggested, only females. Furthermore, how much protection may be afforded is unknown. Here we report that, in two large case-control studies of over 2,000 African children, the common African form of G6PD deficiency (G6PD A-) is associated with a 46-58% reduction in risk of severe malaria for both female heterozygotes and male hemizygotes. A mathematical model incorporating the measured selective advantage against malaria suggests that a counterbalancing selective disadvantage, associated with this enzyme deficiency, has retarded its rise in frequency in malaria-endemic regions. Although G6PD deficiency is now regarded as a generally benign disorder, in earlier environmental conditions it could have been significantly disadvantageous.

Analysis of connectivity in the cat cerebral cortex.

Abstract: The mammalian cerebral cortex is innervated by a large number of corticocortical connections. The number of connections makes it difficult to understand the organization of the cortical network. Nonetheless, conclusions about the organization of cortical systems drawn from examining connectional data have often been made in a speculative and informal manner, unsupported by any analytic treatment. Recently, progress has been made toward more systematic ways of extracting organizing principles from data on the network of connections between cortical areas of the monkey. In this article, we extend these approaches to the cortical systems of the cat. We collated information from the neuroanatomical literature about the corticocortical connections of the cat. This collation incorporated 1139 reported corticocortical connections between 65 cortical areas. We have previously used an optimization technique (Scannell and Young, 1993) to analyze this database in order to represent the connectional organization of cortical systems in the cat. Here, we report the connectional database and analyze it in a number of further ways. First, we employed rules from Felleman and Van Essen (1991) to investigate hierarchical relations among the areas. Second, we compared quantitatively the results of the optimization method with the results of the hierarchical method. Third, we examined quantitatively whether simple connection rules, which may reflect the development and evolution of the cortex, can account for the experimentally identified corticocortical connections in the database. The results showed, first, that hierarchical rules, when applied to the cat visual system, define a largely consistent hierarchy. Second, in both auditory and visual systems, the ordering of areas by hierarchical analysis and by optimization analysis was statistically significantly related. Hence, independent analyzes concur broadly in their ordering of areas in the cortical hierarchies. Third, the majority of corticocortical connections, and much of the pattern of connectivity, were accounted for by a simple “nearest-neighbor-or-next-door-but-one” connection rule, which may suggest one of the mechanisms by which the development of cortical connectivity is controlled.

The mathematics of financial derivatives : a student introduction

Abstract: Finance is one of the fastest growing areas in the modern banking and corporate world. This, together with the sophistication of modern financial products, provides a rapidly growing impetus for new mathematical models and modern mathematical methods; the area is an expanding source for novel and relevant 'real-world' mathematics. In this book the authors describe the modelling of financial derivative products from an applied mathematician's viewpoint, from modelling through analysis to elementary computation. A unified approach to modelling derivative products as partial differential equations is presented, using numerical solutions where appropriate. Some mathematics is assumed, but clear explanations are provided for material beyond elementary calculus, probability, and algebra. Over 140 exercises are included. This volume will become the standard introduction to this exciting new field for advanced undergraduate students.