Biomedical subjects

Stephen Turner

Publications and source records attributed to Stephen Turner.

13 recordsLinked to original sources

PubMed2006

Short-term cardiac memory and mother rotor fibrillation.

Short-term cardiac memory refers to the effects of pacing history on action potential duration (APD). Although the ionic mechanisms for short-term memory occurring over many heartbeats (also called APD accommodation) are poorly understood, they may have important effects on reentry and fibrillation. To explore this issue, we incorporated a generic memory current into the Phase I Luo and Rudy action potential model, which lacks short-term memory. The properties of this current were matched to simulate quantitatively human ventricular monophasic action potential accommodation. We show that, theoretically, short-term memory can resolve the paradox of how mother rotor fibrillation is initiated in heterogeneous tissue by physiological pacing. In simulated heterogeneous two-dimensional tissue and three-dimensional ventricles containing an inward rectifier K(+) current gradient, short-term memory could spontaneously convert multiple wavelet fibrillation to mother rotor fibrillation or to a mixture of both fibrillation types. This was due to progressive acceleration and stabilization of rotors as accumulation of memory shortened APD and flattened APD restitution slope nonuniformly throughout the tissue.

Action Potentials↗

PubMed2006

Effectiveness of educational interventions in improving detection and management of dementia in primary care: cluster randomised controlled study.

OBJECTIVE: To test the effectiveness of educational interventions in improving detection rates and management of dementia in primary care. DESIGN: Unblinded, cluster randomised, before and after controlled study. SETTING: General practices in the United Kingdom (central Scotland and London) between 1999 and 2002. INTERVENTIONS: Three educational interventions: an electronic tutorial carried on a CD Rom; decision support software built into the electronic medical record; and practice based workshops. PARTICIPANTS: 36 practices participated in the study. Eight practices were randomly assigned to the electronic tutorial; eight to decision support software; 10 to practice based workshops; and 10 to control. Electronic and manual searches yielded 450 valid and usable medical records. MAIN OUTCOME MEASURES: Rates of detection of dementia and the extent to which medical records showed evidence of improved concordance with guidelines regarding diagnosis and management. RESULTS: Decision support software (P = 0.01) and practice based workshops (P = 0.01) both significantly improved rates of detection compared with control. There were no significant differences by intervention in the measures of concordance with guidelines. CONCLUSIONS: Decision support systems and practice based workshops are effective educational approaches in improving detection rates in dementia.

Aged↗

PubMed2005

DX5/CD49b-positive T cells are not synonymous with CD1d-dependent NKT cells.

NKT cells are typically defined as CD1d-dependent T cells that carry an invariant TCR alpha-chain and produce high levels of cytokines. Traditionally, these cells were defined as NK1.1+ T cells, although only a few mouse strains express the NK1.1 molecule. A popular alternative marker for NKT cells has been DX5, an Ab that detects the CD49b integrin, expressed by most NK cells and a subset of T cells that resemble NKT cells. Interpretation of studies using DX5 as an NKT cell marker depends on how well DX5 defines NKT cells. Using a range of DX5 and other anti-CD49b Abs, we reveal major differences in reactivity depending on which Ab and which fluorochrome are used. The brightest, PE-conjugated reagents revealed that while most CD1d-dependent NKT cells expressed CD49b, they represented only a minority of CD49b+ T cells. Furthermore, CD49b+ T cell numbers were near normal in CD1d-/- mice that are completely deficient for NKT cells. CD1d tetramer- CD49b+ T cells differ from NKT cells by their activation and memory marker expression, tissue distribution, and CD4/CD8 coreceptor profile. Interestingly, both NKT cells and CD1d tetramer- CD49b+ T cells produce cytokines, but the latter are clearly biased toward Th1-type cytokines, in contrast to NKT cells that produce both Th1 and Th2 cytokines. Finally, we demonstrate that expression of CD49b by NKT cells does not dramatically alter with age, contrasting with earlier reports proposing DX5 as a maturation marker for NKT cells. In summary, our data demonstrate that DX5/CD49b is a poor marker for identifying CD1d-dependent NKT cells.

Animals↗

PubMed2005

Using cell potential energy to model the dynamics of adhesive biological cells.

Developing a continuous mathematical model of a physical phenomenon which is based on a discrete model of the same system is not straightforward. Yet such a process is useful in illustrating the link between the individual behavior of the elements comprising a system and its macroscopic behavior. Collections of biological cells can exhibit phenomena such as pattern formation, aggregation, and invasion, and mathematics has proven useful in elucidating the underlying dynamics of these phenomena. The continuous models formulated are frequently of reaction-diffusion form, and central to their application is a knowledge of the diffusion coefficient of a collection of the elements comprising the system. Cohen and Murray [J. Math Biol. 12, 237 (1981)] developed a means of deriving this quantity which has since been largely neglected by model developers, and which is based on a knowledge of the potential energy associated with the mutual interaction between the cells. In this work, we begin by deriving the energy of interaction of biological cells modeled as adhesive, deformable spheres. In so doing, we are able to quantify the equilibrium density of a biological cell aggregate, and also obtain a quantitative estimate of the diffusion coefficient of a collection of cells modeled in this way. In so doing, we are able to use experimental data from single-cell studies of the adhesiveness and cell membrane elasticity of a biological cell to derive the diffusion coefficient of a cell mass composed of a collection of identical cells. This allows us to better inform the parameter values used in reaction-diffusion models of biological systems. We go on to apply this technique to a particular situation: modeling the dynamics of a collection of biological cells which experience strong cell-cell adhesion. In so doing, we derive a nonlinear fourth-order partial differential equation to model this system. We conclude by discussing the practical utility of this work in illuminating the link between the microscopic behavior of individual biological cells and the macroscopic behavior of the aggregate to which they give rise, and also by giving some insights into how the modeling of cell-cell adhesion may be treated mathematically.

Animals↗

PubMed2005

WASP- mice exhibit defective immune responses to influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis BCG.

OBJECTIVE: To quantify the immune response of WASP- mice to three different pathogens: influenza A virus, Streptococcus pneumoniae, and Mycobacterium bovis. METHODS: Primary and secondary T-cell responses to influenza A virus were quantified via tetramer assays. Viral clearance from lung was also measured. Lethality of intranasal inoculation with luminescent S. pneumoniae was assessed by dose escalation and direct luminescence imaging. After intravenous inoculation with M. bovis, residual mycobacteria in lung, liver, and spleen were measured by standard culture methods. RESULTS: The reduced secondary T-cell response to influenza A virus correlates with a relative but not absolute loss of splenic T and B cells similar to that seen in clinical Wiskott-Aldrich Syndrome (WAS), and slower clearance of virus from lung. The reduced magnitude of the secondary T-cell response correlates with a progressive loss of influenza-specific T cells after primary inoculation. WASP- mice show an increased susceptibility to lethal pneumonia after intranasal inoculation with S. pneumoniae, which is among the most frequent causes of clinical complications in WAS patients. WASP- mice clear M. bovis bacille Calmette-Guerin (BCG) more slowly from lung, liver, and spleen. Bone marrow-derived macrophages, however, show normal ex vivo cytokine secretion in response to M. bovis. CONCLUSIONS: These results demonstrate that WASP- mice are functionally immunodeficient in regard to three different pathogens, and provide relevant end points for the study of treatment modalities in this model. They also suggest a specific physiologic mechanism, failure to accumulate memory T cells, for at least one of the defective immune responses.

Animals↗

PubMed2004

General practitioners' knowledge, confidence and attitudes in the diagnosis and management of dementia.

OBJECTIVE: To measure general practitioners' knowledge of, confidence with and attitudes to the diagnosis and management of dementia in primary care. SETTING: 20 general practices of varying size and prior research experience in Central Scotland, and 16 similarly varied practices in north London. PARTICIPANTS: 127 general practitioners who had volunteered to join a randomised controlled trial of educational interventions about dementia diagnosis and management. METHODS: Self-completion questionnaires covering knowledge, confidence and attitudes were retrieved from practitioners prior to the educational interventions. RESULTS: General practitioners' knowledge of dementia diagnosis and management is good, but poor awareness of its epidemiology leads to an over-estimate of caseload. Knowledge of local diagnostic and support services is less good, and one third of general practitioners expressed limited confidence in their diagnostic skills, whilst two-thirds lacked confidence in management of behaviour and other problems in dementia. The main difficulties identified by general practitioners were talking with patients about the diagnosis, responding to behaviour problems and coordinating support services. General practitioners perceived lack of time and lack of social services support as the major obstacles to good quality care more often than they identified their own unfamiliarity with current management or with local resources. Attitudes to the disclosure of the diagnosis, and to the potential for improving the quality of life of patients and carers varied, but a third of general practitioners believed that dementia care is within a specialist's domain, not that of general practice. More experienced and male general practitioners were more pessimistic about dementia care, as were general practitioners with lower knowledge about dementia. Those reporting greater difficulty with dementia diagnosis and management and those with lower knowledge scores were also less likely to express attitudes endorsing open communication with patient and carer. CONCLUSION: Educational support for general practitioners should concentrate on epidemiological knowledge, disclosure of the diagnosis and management of behaviour problems in dementia. The availability and profile of support services, particularly social care, need to be enhanced, if earlier diagnosis is to be pursued as a policy objective in primary care.

Aged↗

PubMed2004

Tamoxifen treatment failure in cancer and the nonlinear dynamics of TGFbeta.

The process of cancer invasion involves a complex interplay between cell-cell and cell-medium adhesion, proteolytic enzyme secretion, cell birth and death processes, random and directed motility, and immune response, as well as many other factors. The growth factor TGF beta is known to have a complex effect on this process. It inhibits mitosis and promotes apoptosis in a concentration-dependent manner in vitro, and it is for this reason that its secretion is thought to be helpful in inhibiting tumour growth. However, recent in vitro and in vivo results have shown a significant effect of this growth factor in promoting the sensitivity of malignantly transformed cells to gradients of extracellular matrix proteins--an effect which tends to increase invasiveness. The drug tamoxifen has been demonstrated to be therapeutically effective in the treatment of patients with breast cancer; however, it is known also that many patients become resistant to the effect of this drug after a few years, and the reasons for this remain controversial. In this work we take our established model of cancer invasion (J. Theor. Biol. 216(1) (2002) 85), and extend it to include the effect of TGF beta. In so doing we demonstrate that a tamoxifen-stimulated upregulation of the secretion of TGF beta may give rise to a tumour which has a smaller number of cells but which has a greater invasiveness, greater metastatic potential, and a tumour histology which is known to correlate with a poorer prognosis. These data suggest that tamoxifen-stimulated secretion of TGF beta might explain treatment failure in some patients.

Anticarcinogenic Agents↗

PubMed2004

From a discrete to a continuous model of biological cell movement.

The process by which one may take a discrete model of a biophysical process and construct a continuous model based upon it is of mathematical interest as well as being of practical use. In this work, we take the extended Potts model applied to biological cell movement to its continuous limit. Beginning with a single cell moving in one dimension on a lattice and obeying Potts model rules of movement we develop an expression for the diffusion coefficient of a collection of noninteracting cells which depends explicitly on the Potts model parameters. We show how this coefficient varies when the Potts parameters for cell membrane elasticity and cell-medium adhesion are varied, and perform computer simulations which support our theoretical result. We explain the relationship between the probability of occupancy of lattice points and the density profile in the continuous limit, and extend our analysis by including interactions between the cells. In so doing we are able to develop a set of coupled ordinary differential equations showing the evolution of a density profile in the presence of significant cell-cell adhesion, and show how increases in the strength of this adhesion modulates diffusion. In so doing we develop some insights into how continuous models of physical systems can be based upon discrete models which describe the same system.

Animals↗

PubMed2003

A genome-wide scan for urinary albumin excretion in hypertensive families.

Albuminuria increases the risk of cardiovascular events in patients with essential hypertension and diabetic subjects. The heritability (h2) of albuminuria in multiplex hypertensive families is unknown. We calculated the familial aggregation of urine albumin:creatinine ratio (ACR) and performed a genome-wide scan to assess for loci contributing to ACR in participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN). To perform the genome scan, we analyzed genotype results from 2589 individuals from 805 families in the Family Blood Pressure Program. ACR and covariates were available in 1727 individuals (mean age, 57.1 years). Estimates of h2 were obtained by using variance component methodology as implemented in the SOLAR software package. Linkage was tested between 387 markers spanning the genome at an average interval of 9.32 cM, using SOLAR multipoint analysis. The h2 of log urine ACR was 0.49 (P<1x10(-7)) after controlling for significant main and interactive effects of age, gender, race, body mass index, blood pressure, and use of ACE inhibitors or angiotensin-2 receptor blockers. The genome-wide scan revealed a maximum LOD score of 2.73 on chromosome 19 (robust corrected LOD, 2.40; P=0.0009) at marker D19S591 and a LOD score of 2.0 on chromosome 12 (robust corrected LOD, 1.75; P=0.005) at marker PAH. These analyses demonstrate the marked heritability of urine ACR in families enriched for the presence of members with essential hypertension. They suggest that a gene(s) associated with urinary ACR may be present on human chromosomes 19 and 12.

Adult↗

PubMed2003

Diagnostic tools in linkage analysis for quantitative traits.

Diagnostic methods are key components in any good statistical analysis. Because of the similarities between the variance components approach and regression analysis with respect to the normality assumption, when performing quantitative genetic linkage analysis using variance component methods, one must check the normality assumption of the quantitative trait and outliers. Thus, the main purposes of this paper are to describe methods for testing the normality assumption, to describe various diagnostic methods for identifying outliers, and to discuss the issues that may arise when outliers are present when using variance components models in quantitative trait linkage analysis. Data from the Rochester Family Heart Study are used to illustrate the various diagnostic methods and related issues.

Coronary Artery Disease↗

PubMed2003

NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children.

Exhaled nitric oxide (FENO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FENO in adults with asthma and cystic fibrosis, was associated with the raised FENO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6-18 years) underwent measurements of FENO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FENO in either the whole sample of healthy children (n = 87) or in the subsample of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FENO.

Adolescent↗

PubMed2003

Academic attainments of children with Down's syndrome: a longitudinal study.

BACKGROUND: Studies of the academic progress of schoolchildren with Down's syndrome have given only limited indication of attainments at different ages. Such normative data, it is argued, could guide professionals and parents in respect to reasonable expectations and typical achievement. AIMS: The aim of the paper is to provide a descriptive account of levels and range of academic attainments reached by a representative sample of children with Down's syndrome over time. SAMPLE: Data relate to 106 children from three studies with the same cohort of families. Mean age was 9.1 years at the first study (1986), 13.7 at the second (1991), and 21.1 at the third (2000). Mean IQ was 40.29. METHODS: The Academic Attainments Index (AAI) covers reading, writing and numeracy, and was designed for teacher completion. In order to compare attainments to wider norms, scores were compiled by age group, and related to age-specific National Curriculum attainment levels, which are similar to US school grades. RESULTS: AAI scores were obtained for 102 individuals in 1986, 101 in 1991 and 79 in 2000. Comparisons across age groups indicate that higher scores were achieved by each successive age group up to age 20, and that this pattern held for both more and less able children. Once adjusted for differences in IQ scores between age groups, however, there was some evidence of a levelling off towards the end of the school career. By school-leaving age, the more able children reached at least some National Curriculum Key Stage 2 targets in reading and writing, and some Key Stage 3 targets in number work. CONCLUSION: Results provide a detailed picture of attainments across ability and age

Adolescent↗

PubMed2002

Intercellular adhesion and cancer invasion: a discrete simulation using the extended Potts model.

We develop a discrete model of malignant invasion using a thermodynamic argument. An extension of the Potts model is used to simulate a population of malignant cells experiencing interactions due to both homotypic and heterotypic adhesion while also secreting proteolytic enzymes and experiencing a haptotactic gradient. In this way we investigate the influence of changes in cell-cell adhesion on the invasion process. We demonstrate that the morphology of the invading front is influenced by changes in the adhesiveness parameters, and detail how the invasiveness of the tumour is related to adhesion. We show that cell-cell adhesion has less of an influence on invasion compared with cell-medium adhesion, and that increases in both proteolytic enzyme secretion rate and the coefficient of haptotaxis act in synergy to promote invasion. We extend the simulation by including proliferation, and, following experimental evidence, develop an algorithm for cell division in which the mitotic rate is explicitly related to changes in the relative magnitudes of homotypic and heterotypic adhesiveness. We show that although an increased proliferation rate usually results in an increased depth of invasion into the extracellular matrix, it does not invariably do so, and may, indeed, cause invasiveness to be reduced.

Algorithms↗