An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment.

Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 µM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

Moving inwards, moving outwards, moving upwards: the role of spirituality during the early stages of breast cancer.

The paper reflects on a study which explored the role of spirituality in the lives of women during the first year after being diagnosed with breast cancer. The study utilised a qualitative method (hermeneutic phenomenology) designed to provide rich and thick understanding of women's experiences of breast cancer and to explore possible ways in which spirituality may, or may not, be beneficial in enabling coping and enhancing quality of life. The paper draws on the thinking of David Hay and Viktor Frankl to develop a model of spirituality that includes, but is not defined by, religion and that has the possibility to facilitate effective empirical enquiry. It outlines a threefold movement - inwards, outwards and upwards - that emerged from in-depth interviews with women who have breast cancer. This framework captures something of the spiritual movement that women went through on their cancer journeys and offers some pointers and possibilities for better and more person-centred caring approaches that include recognition of the spiritual dimension of women's experiences for the management of those with breast cancer.

Vaccination in pulses: a strategy for global eradication of measles and polio?

Recent American successes against poliomyelitis and measles have been attributed to repeated 'pulse' vaccination campaigns. Whilst logistic and economic constraints will be crucial, a deeper epidemiological understanding of the mechanism, strengths and weaknesses of pulse vaccination will optimize the chances of success elsewhere in the world.

Theoretical studies of the effects of heterogeneity in the parasite population on the transmission dynamics of malaria.

Periodicity in malaria transmission has generally been ascribed to seasonal fluctuations in mosquito population density or spatial heterogeneity with periodic migration. In this paper we demonstrate that simple models of strain heterogeneity can generate periodic behaviour as a consequence of the interaction between parasite strains and host immunological defences. As the degree of cross-immunity between strains increases, the system moves from a régime of independent strain transmission and coexistence, through increasingly coupled behaviour, to the displacement of the strain of lower transmissibility by the strain with a higher basic reproductive rate (R0). Cross-immunity thus serves both to bring the strains into competition, and also to couple the dynamics. We find analytical and numerical results on strain coexistence to show how the range of possible outcomes may be read as an effect of the tension between these two effects of cross-protection.

Potential impact of low efficacy HIV-1 vaccines in populations with high rates of infection.

A safe and effective HIV vaccine to prevent infection and/or to moderate disease is urgently needed. Research progress has been slower than anticipated for a variety of reasons including uncertainty over which immunogen to use (i.e. recombinant subunit envelope proteins or whole HIV-1 products), confusion on which immunological markers best correlate with protection, the relevance of the HIV-1 chimpanzee model to infection in humans and the significance of the rapid evolution of HIV-1, with different clades of the virus emerging in different parts of the world. However, what some would interpret as encouraging results, from Phase I and II trials of recombinant envelope glycoprotein vaccines, have raised the question of whether the time is right to start Phase III trials in humans with immunogens that may have low to moderate efficacy. By using mathematical models and data from epidemiological studies, we examine the potential impact of such vaccines within heterosexual communities with high rates of infection. Analyses suggest that it will be difficult to block HIV-1 transmission even with very high levels of mass vaccination. The cost of sustaining high levels of herd immunity with a vaccine of short protection duration is likely to be high. However, assessments of impact over the long duration of an HIV-1 epidemic indicate that many cases of HIV infection and associated mortality can be prevented by immunogens with efficacy of 50% or less and a five year protection duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonococcal infection and human fertility in sub-Saharan Africa.

An analysis is presented of the influence of Neisseria gonorrhoeae on human population growth in regions of sub-Saharan Africa where gonococcal infections are prevalent in sexually active adults. Combining epidemiological and demographic data within the framework of a mathematical model, we show that gonorrhoea has a major impact on fertility and, concomitantly, on net population growth in areas with a high prevalence of untreated infections. Specifically, a 20% prevalence in sexually active adults is predicted to induce a 50% reduction in net population growth. Model predictions are in good agreement with observed data from Uganda, and the sensitivity of the prediction to various complications, such as heterogeneity in sexual behaviour, is assessed. The analysis suggests that the predicted increase in fertility arising from expanded sexually transmitted disease (STD) control programmes in Africa to help combat the spread of human immunodeficiency viruses (HIV-1 and HIV-2) will help to offset the predicted demographic impact of AIDS in the worst afflicted areas. In other areas the rise in fertility associated with effective STD control will need to be countered by the linkage of STD control programmes with family planning initiatives.

Isolation and experimental chicken-embryo-inoculation studies with budgerigar papovavirus.

Attempts to isolate and identify budgerigar papovavirus (BPV) were made during three separate outbreaks of disease diagnosed on pathological grounds. Direct electron microscopy was successful only when large areas of skin were extensively disrupted to release virus and then extracted with fluorocarbon to remove lipids. Direct inoculation of budgerigar tissue suspensions into chicken embryos or chicken cell cultures failed to produce detectable virus. However, when primary cultures of liver and kidney were prepared from affected budgerigars, BPV could be detected by electron microscopy and by the production of a cytopathic effect at the third or fourth passage in cell cultures. The isolated virus was pathogenic for 10-day-old but not 11- or 12-day-old chicken embryos. Inoculated 11- and 12-day-old embryos produced antibodies to BPV that were detectable 2 weeks after hatching by agar-gel-immunodiffusion tests.

The suitability of immunosuppressed mice kept in a standard animal unit as recipients of human tumour xenografts.

CBA/Lac mice were immunosuppressed by thymectomy and whole body irradiation with 250 kVp X-rays following pretreatment with cytosine arabinoside. The optimum radiation dose for immunosuppression with prolonged survival was 7.35 Gy. The animals were kept in a standard animal unit with an overall survival rate of 83%. They were found to be suitable for large scale, long-term, xenotransplantation experiments at 20% of the cost of nude mice.

Community, culture and character: the place of the virtues in psychiatric nursing practice.

In this paper, the authors address the serious neglect of the 'classical' virtues in ethical reflection upon mental health nursing. The virtues are offered as a possible alternative paradigm for mental health nursing in its search for new models and approaches. Embodied in the notion of a moral community, the virtues have important implications in addressing problems adherent in various 'dualisms' so described. By invoking the concepts of practical wisdom and praxis, the interrelationship between theory and practice, action and reflection and self and community, is shown. The contextual nature of the virtues is shown in a number of examples and their potential for the transformation of practice is shown. The opportunity is now present for mental health nursing to strengthen its basis for practice by distancing itself from scientific models. In so doing, it can embrace an approach which is consensual and contextual and which places ethical reflection at the centre of practice.

Spirituality. Come all ye faithful.

A growing body of research suggests that religion and spirituality can have a positive effect on mental and physical health. Like any other powerful belief system, they also have potential for harm. Further research is needed if they are to be understood and therapeutically incorporated into healthcare.

Decreased internalisation of erbB1 mutants in lung cancer is linked with a mechanism conferring sensitivity to gefitinib.

A majority of gefitinib (IRESSA)-responsive tumours in non-small cell lung cancer have been found to carry mutations in ErbB1. Previously, it has been observed that internalisation-deficient ErbB1 receptors are strong drivers of oncogenesis. Using a computational model of ErbB1 trafficking and signalling, it is found that a deficiency in ErbB1 internalisation is sufficient to explain the observed signalling phenotype of these gefitinib-responsive ErbB1 mutants in lung cancer cell lines. Experimental tests confirm that gefitinib-sensitive cell lines with and without ErbB1 mutations exhibit markedly slower internalisation rates than gefitinib-insensitive cell lines. Moreover, the computational model demonstrates that reduced ErbB1 internalisation rates are mechanistically linked to upregulated AKT signalling. Experimentally it is confirmed that impaired internalisation of ErbB1 is associated with increased AKT activity, which can be blocked by gefitinib. On the basis of these experimental and computational results, it is surmised that gefitinib sensitivity is a marker of a reliance on AKT signalling for cell survival that may be brought about by impaired ErbB1 internalisation.

Extinction times and phase transitions for spatially structured closed epidemics.

This paper considers the time to extinction for a stochastic epidemic model of SEIR form without replacement of susceptibles. It first shows how previous rigorous results can be heuristically explained in terms of the more transparent dynamics of an approximating deterministic system. The model is then extended to include a host population structured into patches, with weak nearest-neighbour mixing of infection. It is shown, by considering the approximating deterministic system, that the expected time to extinction in a population of n + 1 patches each of size N is of the form a log N + bn, provided that N > Nc where Nc is a critical patch size below which transits are unlikely to occur. This corresponds to the simple decomposition of the time of an epidemic into the time it takes to spread through one patch plus the time it takes to transit to each of n successive patches. Expressions for this threshold and the coefficients of the time to extinction are given in terms of the transmission parameters of infection and the coupling strength between patches. These expressions are compared with numerical results using parameters relevant to a study of phocine distemper virus in North Sea seals, and the agreement is found to be good for large and small N. In the region when N approximately Nc, where transits may or may not occur, interesting transitional behaviour is seen, leading to a non-monotonicity of the extinction time as a function of N.

A status-based approach to multiple strain dynamics.

We present and investigate a new model for cross-immunity. Past models classify hosts according to their infection history. Here we represent hosts through their status: their current ability to respond to strains. This framework allows a different, a wider, and a more biologically interpretable range of forms of cross-immunity to be studied. Using this new form of cross-immunity we then consider a previously studied case of four strains, each of which confers partial immunity to two of the others. In this interesting special case, with applications to the genetic maintenance of strain diversity, we can make substantial analytical progress. We present methods for exploiting the symmetries of the system to show that only a particular invariant subspace need be considered for characterizing the dynamics of the whole system. A complete bifurcation structure is given for this subspace. In contrast to systems previously studied, this system does not exhibit sustained oscillations for any set of parameter values.

The control of childhood viral infections by pulse vaccination.

Pulse vaccination, the repeated application of vaccine over a defined age range, is gaining prominence as a strategy for the elimination of childhood viral infections such as measles and polio. However, unlike routine or continuous mass infant immunization, epidemiological understanding of this control method is in its infancy. This paper develops initial work by Agur et al. (1993) using simple steady-state and age-structured dynamic models to extend the theory of the mechanism of action of pulse vaccination, and to explore the relationship between the maximum permitted interval between pulses and key epidemiological, demographic and vaccination variables. Initially, a conceptual model is presented to illustrate the principles of pulse vaccination and to make comparison with routine immunization procedures. An ordinary differential equation model, which assumes homogeneous mixing, is then used to derive equilibrium expressions for the pulse interval in relation to (i) different demographic profiles, (ii) population growth characteristics (stationary or exponentially increasing), (iii) combined routine and pulse immunization, and (iv) the age range vaccinated. Finally, simulations using age-structured compartmental deterministic models illustrate complex epidemiological dynamics associated with pulse vaccination, particularly where there is age heterogeneity in contact rates in the population. The resultant uncertainty in defining an optimal pulse interval raises concerns of a practical nature.

The role of sexual partnership networks in the epidemiology of gonorrhea.

BACKGROUND: Empirical studies have the potential to collect data on patterns of sexual mixing and network structures. GOAL: To explore the contribution of different network measures in sexually transmitted disease epidemiology. STUDY DESIGN: Individual-based stochastic simulations of a network of sexual partnerships and sexually transmitted disease transmission are analyzed using logistic regression. RESULTS AND CONCLUSIONS: Measures accumulated over times similar to the duration of infection are more informative than are static cross sections. The patterns of sexual mixing and network structure influence patterns of infection. In particular, the establishment of infection is most sensitive to the proportion of nonmonogamous pairs, the component distribution and cohesion among those with high activity. The subsequent prevalence is most sensitive to the assortativeness of mixing in the high-activity class and a measure of cohesion, both of which reflect the decrease in prevalence brought about by less widespread connections. A person's risk for infection is determined by local rather than global network structures.

Dynamic interaction between Leishmania infection in mice and Th1-type CD4+ T-cells: complexity in outcome without a requirement for Th2-type responses.

The interaction between Leishmania parasites and Th1 cells is investigated using a simple mathematical model of immunological responses and parasite population growth within the host. The model generates patterns of resistance and susceptibility to infection that mirror observed trends in experimental infections of mice and of humans exposed to infection in areas of endemic transmission. The heterogeneity in outcome predicted by the model can arise either through differences in the values of the parameters that characterize the genetic background of the host or as a consequence of differences in the size of the infecting inoculum of the parasite. Detailed analyses of equilibrium states and of the time course of infection within a host suggest that a limitation in the availability of precursor T-cells, as a consequence of high levels of recruitment into the activated pool, may play a significant role in the progression of infection in susceptible hosts. A brief discussion is presented of the implications of model prediction for therapeutic intervention.

Two signal activation as an explanation of high zone tolerance: a mathematical exploration of the nature of the second signal.

Much work on the induction of non-responsiveness in lymphocytes suggests that it takes two signals to activate a cell correctly, and that receipt of the first signal alone not only causes suboptimal response, but also subsequent non-responsiveness or anergy. This paper discusses not anergy, but the original suboptimal response in the context of the well known but poorly understood phenomenon of high zone tolerance in experiments studying immunological responses to a range of antigen concentrations (low to high "zones"). We proceed to ask specific questions about the nature and timing of the signals involved. We construct three different models describing how the second signal might be received and use them to predict the shapes of dose-response curves. Comparison with data enables us to select, from a dynamical perspective, the most likely mechanism and to tentatively exclude a number of proposed mechanisms for high zone tolerance. We suggest that the stage at which a cell becomes susceptible to anergy is crucial and that it is over-contact, rather than lack of contact, which is important in the induction of tolerance.