PubMed Health⌕ Search

Biomedical subjects

R M Seymour

Publications and source records attributed to R M Seymour.

13 recordsLinked to original sources
PubMed2004

TNF-alpha neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome.

OBJECTIVES: Neutralization of TNF-alpha with either monoclonal antibodies or soluble receptors, although not curative, has significant clinical benefit in patients with rheumatoid arthritis (RA). In contrast, blockade of TNF-alpha has little clinical benefit in the majority of patients with systemic inflammatory response syndrome (SIRS) in spite of the identification of TNF-alpha as a key factor in its pathology. It is not clear why there is such a significant difference in the responses to TNF-alpha neutralization in these two conditions. Here we use mathematical modelling to investigate this discrepancy. METHODS: Using the known pharmacokinetic and pharmacodynamic properties of TNF-alpha-blocking biological agents, we constructed a mathematical model of the biological actions of soluble(s) TNFR2, Etanercept and Infliximab. RESULTS: Our model predicts that all three inhibitors, but especially Etanercept, are effective at controlling TNF-alpha levels in RA, which we propose is a condition in which TNF-alpha production and inhibition are in equilibrium. However, when free TNF-alpha drops to a low level, as can occur in SIRS, which we propose is a non-equilibrium condition, the sequestered TNF-alpha can act as a slow-release reservoir, thereby sabotaging its effectiveness. CONCLUSIONS: These results may explain the effectiveness of TNF-alpha blockade in the equilibrium condition RA and the ineffectiveness in the non-equilibrium condition SIRS.

Antibodies, Monoclonal↗
PubMed2001

Pro-inflammatory--anti-inflammatory cytokine dynamics mediated by cytokine-receptor dynamics in monocytes.

Many of the major human diseases, both infectious (septic shock syndromes) and idiopathic (for example, rheumatoid arthritis), are driven by the production of the pro-inflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha) produced by monocytes and macrophages. These key pro-inflammatory cytokines can, in turn, stimulate the production of additional cytokines which, in totality, generate tissue pathology. A major deactivator of activated, cytokine-producing monocytes and macrophages is the anti-inflammatory cytokine interleukin-10 (IL-10). It is known that the interactions between these three cytokines are pivotal in terms of health and pathology, but almost nothing is known of the dynamics of these interactions. In this study we have modelled the autocrine interactions of TNF-alpha, IL-1 and IL-10 with monocytes. The model constructed is a six-dimensional, continuous-time dynamical system, with free IL-1 and IL- 10 concentrations in the cell's vicinity, and the proportions of bound and free IL-1 and IL-10 cell-surface receptors, which transduce the cell's response to stimulation, as the state variables. The monocyte is assumed to be initially in a quiescent state, and it is stimulated to produce IL-1 by an external stimulus (e.g. exposure to TNF-alpha or lipopolysaccharide, LPS). This in turn invokes an autocrine IL-1 response, and also induces the production of the anti-inflammatory cytokine IL-10, which acts to downregulate IL-1 production. These responses are mediated by specific cell-surface receptors, the concentrations of which may also be subject to stimulated upregulation. We analyse a reduced, four-dimensional version of the model, and explore its asymptotic states. We find a variety of possible outcomes: runaway IL-1 production, multiple stable equilibria, stable limit cycles, and, exceptionally, quasi-periodic behaviour. These behaviours depend crucially on the form of the cell's response functions. The possible biological implications of these phenomena are discussed.

Arthritis, Rheumatoid↗
PubMed1998

Important drug-drug interactions in the elderly.

Although drug-drug interactions constitute only a small proportion of adverse drug reactions, they are important because they are often predictable and therefore avoidable or manageable. Their frequency is related to the age of the patient, the number of drugs prescribed, the number of physicians involved in the patient's care and the presence of increasing frailty. The most important mechanisms for drug-drug interactions are the inhibition or induction of drug metabolism, and pharmacodynamic potentiation or antagonism. Interactions involving a loss of action of one of the drugs are at least as frequent as those involving an increased effect. It is likely that only about 10% of potential interactions result in clinically significant events and, while death or serious clinical consequences are rare, low-grade, clinically unspectacular morbidity in the elderly may be much more common. Nonspecific complaints (e.g. confusion, lethargy, weakness, dizziness, incontinence, depression, falling) should all prompt a closer look at the patient's drug list. There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for each individual should be limited to as few as is necessary. The use of drugs should be reviewed regularly and unnecessary agents withdrawn if possible, with subsequent monitoring. Patients should be encouraged to engage in a 'prescribing partnership' by alerting physicians, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. Physicians with a responsibility for elderly people in an institutional setting should develop a strategy for monitoring their drug treatment. For those interactions that have come to clinical attention, it is important to review why they happened and to plan for future prevention. Clinicians should also report, via the appropriate postmarketing surveillance scheme, any drug-drug interactions they have encountered. Finally, multidisciplinary education about the nature of physiological aging and its effect on drug handling, and the possible presentations of drug-related disease in older patients, is an important element in reducing interactions in the elderly.

Aged↗
PubMed1995

Some aspects of the coevolution of virulence and resistance in contact transmission disease processes with ecological constraints.

In this paper, the author constructs a general, continuous-time dynamical model of a coevolutionary host-microparasite interaction, which incorporates host resistance (degree of susceptibility to invasion by the parasite) and parasite virulence (pathogenicity and transmission efficiency). Discrete classes of resistance type and virulence type are allowed. It is assumed that high virulence parasite strains are able to take over hosts already occupied by lower virulence strains. Heritability of host resistance is assumed, but specific assumptions about the genetics of such inheritance are avoided. Instead, a 'neutral' view is adopted, which assumes that the disease process is the sole selective force acting on a disease-free resistance distribution. This allows the dimensionality of the model to be kept lower than corresponding explicitly population-genetic models. Ecological factors are taken into account via density dependence in host encounter rate (which also influences transmission properties of the disease via contact transmission), and by density dependence in host fecundity. Two distinct host types are considered, which we call 'bunchers' and 'separators', characterized by the form of reaction of the encounter rate to changes in host density. Detailed analyses are given for versions of the model having: (a) one resistance class and one virulence class; (b) two resistance classes and one virulence class; (c) two resistance classes and two virulence classes. Sufficient conditions are found in case (c) for the low resistance type to be eliminated by the coevolutionary process. Features which might tend to promote resistance polymorphism are also discussed.

Animals↗
PubMed1988

A model of myxomatosis based on hormonal control of rabbit-flea reproduction.

A two-dimensional first-order nonlinear system of ordinary differential equations with constant coefficients is constructed to model the rabbit/flea dynamics of the European rabbit viral disease known as myxomatosis. It is proved that infected fleas induce stable oscillations of small amplitude for a range of coefficient values when the Rothschild coupling coefficient r, which models biochemical control of flea reproduction by the rabbit, attains a critical (Hopf) value rO. These oscillations may lead to rapid local extinction of rabbits depending on the virulence gamma 2 of myxoma. The coefficient gamma 1 = r gamma 2 measures the effect on the fleas. Since the four determining coefficients may change over evolutionary time-scales, the mathematical results together with a natural selection argument proves that virulence gamma 2 attenuates. This has been observed both in Australia and in Great Britain. However, the rabbit flea Spilopsyllus cuniculi is not an effective vector for myxoma in Australia, but is the principal vector in Britain, as verified by R. Muirhead-Thomson at the suggestion of M. Rothschild. This preliminary model assumes density-independent rabbit reproductivity pR, but the qualitative results hold for a wider class of density-dependent models. Yet, the former condition is basic for the technique of parameter reduction used to simplify statistical estimation of the more general density-dependent model.

Animals↗
PubMed1975

Scanning and transmission electron microscope studies of interkinetic nuclear migration in the cerebral vesicles of the rat.

A scanning electron microscope (SEM) was used to examine the morphology and surface texture of neuroepithelial cells during interkinetic nuclear migration in the cerebral vesicles of the rat at 12, 13 and 14 days of gestation. Serial sections of embryonic material of the same age were also prepared for the transmission electron microscope (TEM). Particular attention was paid to the SEM and TEM appearance of mitotic neuroepithelial cells which occur exclusively along the ventricular border of the neural epithelium. Three distinctly-shaped classes of mitotic cells were recognised in scanning micrographs. (1) Pyriform cells. This type of mitotic cell was characterised by the presence of very long, fine processes radiating from the tip and shoulders of a short external (basal) process. These fine processes were termed "intramitotic filopodia." Microvilli were found on the surface of most pyriform cells. (2) Conical cells. These lacked an external process but there were large numbers of intramitotic filopodia at the basal pole of the cell body, and the perikaryal surface was rich in microvilli. (3) Globular cells. It was possible to subdivide this class of cell into large and small sizes, but usually a few short intramitotic filopdia were present at the basal pole. The perikaryal surfaces of the globular population were raised in coarse lumps and bubble-like protrusions. By pooling TEM and SEM information we were able to deduce that pyriform cells probably possess a prophase or prometaphase chromosome morphology, while conical cells exhibit a chromosome morphology somewhere between prometaphase and early anaphase. Large globular mitotic cells were found to be between metaphase and late anaphase and small globular cells were identified as early telophase cells. On the basis of these findings we have proposed that as a bipolar neuroepithelial cell rounds up for mitosis it passes first through a pyriform stage during which the external process is retracted or broken down, and then through a conical stage when the cell consolidates its position on the ventricular surface. Finally, the cell enters a large globular stage before dividing into two small globular telophase cells. It is not known what part, if any, the intramitotic filopodia play in this process of rounding up.

Animals↗