Interleukin-4 receptor alpha gene variants and allergic disease

The interleukin-4 (IL-4) signalling cascade has been identified as a pathway potentially important in the development of asthma. Genetic variants within this signalling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor alpha (IL-4Ralpha) gene. In addition polymorphism occurs in the promoter for the IL-4 gene itself. This commentary accompanies a paper by C Ober et al describing the contribution of IL-4Ralpha polymorphism to susceptibility to asthma and atopy in the Hutterite population and other outbred populations collected during the collaborative studies on the genetics of asthma (CSGA) programme

Pharmacogenetics, pharmacogenomics and airway disease

The availability of a draft sequence for the human genome will revolutionise research into airway disease. This review deals with two of the most important areas impinging on the treatment of patients: pharmacogenetics and pharmacogenomics. Considerable inter-individual variation exists at the DNA level in targets for medication, and variability in response to treatment may, in part, be determined by this genetic variation. Increased knowledge about the human genome might also permit the identification of novel therapeutic targets by expression profiling at the RNA (genomics) or protein (proteomics) level. This review describes recent advances in pharmacogenetics and pharmacogenomics with regard to airway disease

Variations in chemoprophylaxis for meningococcal disease: a retrospective case note review, analysis of routine prescribing data and questionnaire of general practitioners

BACKGROUND: Invasive meningococcal disease is a significant cause of mortality and morbidity in the UK. Administration of chemoprophylaxis to close contacts reduces the risk of a secondary case. However, unnecessary chemoprophylaxis may be associated with adverse reactions, increased antibiotic resistance and removal of organisms, such as Neisseria lactamica, which help to protect against meningococcal disease. Limited evidence exists to suggest that overuse of chemoprophylaxis may occur. This study aimed to evaluate prescribing of chemoprophylaxis for contacts of meningococcal disease by general practitioners and hospital staff. METHODS: Retrospective case note review of cases of meningococcal disease was conducted in one health district from 1st September 1997 to 31st August 1999. Routine hospital and general practitioner prescribing data was searched for chemoprophylactic prescriptions of rifampicin and ciprofloxacin. A questionnaire of general practitioners was undertaken to obtain more detailed information. RESULTS: Prescribing by hospital doctors was in line with recommendations by the Consultant for Communicable Disease Control. General practitioners prescribed 118% more chemoprophylaxis than was recommended. Size of practice and training status did not affect the level of additional prescribing, but there were significant differences by geographical area. The highest levels of prescribing occurred in areas with high disease rates and associated publicity. However, some true close contacts did not appear to receive prophylaxis. CONCLUSIONS: Receipt of chemoprophylaxis is affected by a series of patient, doctor and community interactions. High publicity appears to increase demand for prophylaxis. Some true contacts do not receive appropriate chemoprophylaxis and are left at an unnecessarily increased risk

Pathological validation and significance of micrometastasis in sentinel nodes in primary breast cancer

In embracing a multidisciplinary approach to the management of patients with sentinel node biopsy in breast cancer, the pathologist task is to screen sentinel nodes for possible metastasis. The consequences of missing sentinel node micrometastasis can directly influence treatment strategies, and this screening therefore has to be performed with more attention than usual. There is presently great diversity in the histopathological work-up of sentinel nodes, with many centres employing additional techniques such as immunohistochemistry, reverse transcription polymerase chain reaction or flow cytometry in addition to routine haematoxylin and eosin staining. In this review, we address the pathological validation and significance of micrometastasis in sentinel node biopsy in primary breast cancer

Angiogenesis in the pathogenesis of inflammatory joint and lung diseases

This paper reviews hypotheses about roles of angiogenesis in the pathogenesis of inflammatory disease in two organs, the synovial joint and the lung. Neovascularisation is a fundamental process for growth and tissue repair after injury. Nevertheless, it may contribute to a variety of chronic inflammatory diseases, including rheumatoid arthritis, osteoarthritis, asthma, and pulmonary fibrosis. Inflammation can promote angiogenesis, and new vessels may enhance tissue inflammation. Angiogenesis in inflammatory disease may also contribute to tissue growth, disordered tissue perfusion, abnormal ossification, and enhanced responses to normal or pathological stimuli. Angiogenesis inhibitors may reduce inflammation and may also help to restore appropriate tissue structure and function

Clustering through post inhibitory rebound in synaptically coupled neurons

Post inhibitory rebound is a nonlinear phenomenon present in a variety of nerve cells. Following a period of hyper-polarization this effect allows a neuron to fire a spike or packet of spikes before returning to rest. It is an important mechanism underlying central pattern generation for heartbeat, swimming and other motor patterns in many neuronal systems. In this paper we consider how networks of neurons, which do not intrinsically oscillate, may make use of inhibitory synaptic connections to generate large scale coherent rhythms in the form of cluster states. We distinguish between two cases i) where the rebound mechanism is due to anode break excitation and ii) where rebound is due to a slow T-type calcium current. In the former case we use a geometric analysis of a McKean type model to obtain expressions for the number of clusters in terms of the speed and strength of synaptic coupling. Results are found to be in good qualitative agreement with numerical simulations of the more detailed Hodgkin-Huxley model. In the second case we consider a particular firing rate model of a neuron with a slow calcium current that admits to an exact analysis. Once again existence regions for cluster states are explicitly calculated. Both mechanisms are shown to prefer globally synchronous states for slow synapses as long as the strength of coupling is sufficiently large. With a decrease in the duration of synaptic inhibition both systems are found to break into clusters. A major difference between the two mechanisms for cluster generation is that anode break excitation can support clusters with several groups, whilst slow T-type calcium currents predominantly give rise to clusters of just two (anti-synchronous) populations.

Evans functions for integral neural field equations with Heaviside firing rate function

In this paper we show how to construct the Evans function for traveling wave solutions of integral neural field equations when the firing rate function is a Heaviside. This allows a discussion of wave stability and bifurcation as a function of system parameters, including the speed and strength of synaptic coupling and the speed of axonal signals. The theory is illustrated with the construction and stability analysis of front solutions to a scalar neural field model and a limiting case is shown to recover recent results of L. Zhang [On stability of traveling wave solutions in synaptically coupled neuronal networks, Differential and Integral Equations, 16, (2003), pp.513-536.]. Traveling fronts and pulses are considered in more general models possessing either a linear or piecewise constant recovery variable. We establish the stability of coexisting traveling fronts beyond a front bifurcation and consider parameter regimes that support two stable traveling fronts of different speed. Such fronts may be connected and depending on their relative speed the resulting region of activity can widen or contract. The conditions for the contracting case to lead to a pulse solution are established. The stability of pulses is obtained for a variety of examples, in each case confirming a previously conjectured stability result. Finally we show how this theory may be used to describe the dynamic instability of a standing pulse that arises in a model with slow recovery. Numerical simulations show that such an instability can lead to the shedding of a pair of traveling pulses.

Stromule formation is dependent upon plastid size, plastid differentiation status and the density of plastids within the cell

Stromules are motile extensions of the plastid envelope membrane, whose roles are not fully understood. They are present on all plastid types but are more common and extensive on non-green plastids that are sparsely distributed within the cell. During tomato fruit ripening, chloroplasts in the mesocarp tissue differentiate into chromoplasts and undergo major shifts in morphology. In order to understand what factors regulate stromule formation, we analysed stromule biogenesis in tobacco hypocotyls and in two distinct plastid populations in tomato mesocarp. We show that increases in stromule length and frequency are correlated with chromoplast differentiation, but only in one plastid population where the plastids are larger and less numerous. We used tobacco hypocotyls to confirm that stromule length increases as plastids become further apart, suggesting that stromules optimise the plastid-cytoplasm contact area. Furthermore, we demonstrate that ectopic chloroplast components decrease stromule formation on tomato fruit chromoplasts, whereas preventing chloroplast development leads to increased numbers of stromules. Inhibition of fruit ripening has a dramatic impact on plastid and stromule morphology, underlining that plastid differentiation status, and not cell type, is a significant factor in determining the extent of plastid stromules. By modifying the plastid surface area, we propose that stromules enhance the specific metabolic activities of plastids. This is an electronic version of an Article published in The Plant Journal, August 2004, Volume 39, pp. 655-667. Copyright 2004 Blackwell Publishing Ltd and The Society for Experimental Biology.

Directed percolation in a two dimensional stochastic fire-diffuse-fire model

In this paper we establish, from extensive numerical experiments, that the two dimensional stochastic fire-diffuse-fire model belongs to the directed percolation universality class. This model is an idealized model of intracellular calcium release that retains the both the discrete nature of calcium stores and the stochastic nature of release. It is formed from an array of noisy threshold elements that are coupled only by a diffusing signal. The model supports spontaneous release events that can merge to form spreading circular and spiral waves of activity. The critical level of noise required for the system to exhibit a non-equilibrium phase-transition between propagating and non-propagating waves is obtained by an examination of the \textit{local slope} $\delta(t)$ of the survival probability, $\Pi(t) \propto \exp(- \delta(t))$, for a wave to propagate for a time $t$.

What do universities want from publishing?

At a simple level, universities want publishing to support and further their mission to carry out research and teaching. However at a detailed level there are major differences within and between universities which mean there will be different wants and expectations of publishing. Bearing in mind these complexities, this paper examines universities' various requirements as producers, purchasers and consumers of publications. Some of the key wants of universities include impact, affordability, quality and access. The merits of the established system of subscription-based journal publishing and the emerging system of open-access publishing and dissemination are discussed in relation to universities' wants.

Self-archiving publications

This chapter discusses the historical development, current practice and future prospects of the self-archiving of research papers in open-access repositories (so-called 'e-print archives'). It describes how the development of interoperable e-print repositories in a number of subject communities has shown that self-archiving can benefit academic researchers (and potentially others) by enabling quick and easy access to the research literature and therefore maximising the impact potential of papers. Realising that the possible benefits are high and the technical entry barriers low, many organisations such as universities have recently tried to encourage widespread self-archiving by setting up institutional repositories. However, major barriers to self-archiving remain - most of them cultural and managerial. There are concerns about quality control, intellectual property rights, disturbing the publishing status quo, and workload. Ways in which these issues are currently being addressed are discussed in this chapter. A number of self-archiving initiatives in different countries have been set up to address the concerns and to kick-start e-print repository use. However, issues remain which require further investigation; those discussed in this chapter include discipline differences, definitions of 'publication', versioning problems, digital preservation, costing and funding models, and metadata standards. The ways in which these issues are resolved will be important in determining the future of self-archiving. Possible futures are discussed with particular reference to journal publishing and quality control. If widely adopted, self-archiving might come to assume a central place in the scholarly communication process, but a great deal of restructuring of the process needs to take place before this potential can be realised.

Bumps, breathers, and waves in a neural network with spike frequency adaptation

In this Letter we introduce a continuum model of neural tissue that include the effects of so-called spike frequency adaptation (SFA). The basic model is an integral equation for synaptic activity that depends upon the non-local network connectivity, synaptic response, and firing rate of a single neuron. A phenomenological model of SFA is examined whereby the firing rate is taken to be a simple state-dependent threshold function. As in the case without SFA classical Mexican-Hat connectivity is shown to allow for the existence of spatially localized states (bumps). Importantly an analysis of bump stability using recent Evans function techniques shows that bumps may undergo instabilities leading to the emergence of both breathers and traveling waves. Moreover, a similar analysis for traveling pulses leads to the conditions necessary to observe a stable traveling breather. Direct numerical simulations both confirm our theoretical predictions and illustrate the rich dynamic behavior of this model, including the appearance of self-replicating bumps.