Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are ubiquitous human pathogens. They share with other herpesviruses the ability to establish lifelong latent infection of the host. Periodic reactivation from latency is responsible for most of the clinical disease burden of HSV infection. This review focuses on what we have learned from molecular studies in model systems of HSV latency, and the implications these findings have for treating recurrent HSV disease.

Gene therapy has been applied to the treatment of cancer and metastatic disease for over ten years. Research in this area has utilised multiple gene therapy approaches including targeting tumour suppressor genes and oncogenes, stimulating the immune system, targeted chemotherapy, antiangiogenic strategies, and direct viral oncolysis. In recent years, gene delivery vectors have been developed that selectively target tumour cells through tumour-specific receptors, deletion of certain viral gene sequences, or incorporation of tumour-specific promoter sequences that drive gene expression. Preclinical models have produced promising results, demonstrating significant tumour regression and reduction of metastatic disease. Unfortunately, only limited responses have been observed in clinical trials. The main limitations in treating metastatic disease include poor vector transduction efficiencies and difficulties in targeting remote tumour cells with systemic vector delivery. Currently, various groups are investigating means to improve gene delivery and clinical responses by continuing to modify gene delivery vectors and by concentrating on combination gene therapy and multimodality therapy.

The molecular aetiology of familial susceptibility to disseminated mycobacterial disease, usually involving weakly pathogenic strains of mycobacteria, has now been elucidated in more than 30 families. Mutations have been identified in five genes in the interleukin-12-dependent interferon-γ pathway, highlighting the importance of this pathway in human mycobacterial immunity. Knowledge derived from the study of these rare patients contributes to our understanding of the immune response to common mycobacterial pathogens such as Mycobacterium tuberculosis and Mycobacterium leprae, which remain major public health problems globally. This knowledge can be applied to the rational development of novel therapies and vaccines for these important mycobacterial diseases.

Brain injury following cerebral ischaemia (stroke) involves a complex combination of pathological processes, including excitotoxicity and inflammation leading to necrotic and apoptotic forms of cell death. At the cellular level, excitotoxicity is mediated by glutamate and its cognate receptors, resulting in increased intracellular calcium and free radical production, and eventual cell death. Recent evidence suggests that scaffolding molecules that associate with glutamate receptors at the postsynaptic density allow coupling of receptor activity to specific second messengers capable of mediating excitotoxicity. These findings have important implications in the search for effective neuroprotective therapies in treating stroke.

The complement inflammatory cascade is an essential component of the phylogenetically ancient innate immune response and is crucial to our natural ability to ward off infection. Complement is involved in host defence by triggering the generation of a membranolytic complex (the C5b-9 complex) at the surface of the pathogen. Complement fragments (opsonins; C1q, C3b and iC3b) interact with complement cell-surface receptors (C1qRp, CR1, CR3 and CR4) to promote phagocytosis and a local pro-inflammatory response that, ultimately, contributes to the protection and healing of the host. Complement is of special importance in the brain, where entrance of elements of the adaptive immune system is restricted by a blood–brain barrier. There is now compelling evidence that complement is produced locally in response to an infectious challenge. Moreover, complement biosynthesis and activation also occurs in neurodegenerative disorders such as Alzheimer's, Huntington's and Pick's diseases, and the cytolytic/cytotoxic activities of complement are thought to contribute to neuronal loss and brain tissue damage. However, recent data suggest that at least some of the complement components have the ability to contribute to neuroprotective pathways. The emerging paradigm is that complement is involved in the clearance of toxic cell debris (e.g. amyloid fibrils) and apoptotic cells, as well as in promoting tissue repair through the anti-inflammatory activities of C3a. Knowledge of the unique molecular and cellular innate immunological interactions that occur in the development and resolution of pathology in the brain should facilitate the design of effective therapeutic strategies.

The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) carry the cytogenetic abnormality [t(9;22)(q34;q11)] – a reciprocal translocation that results in the expression of a chimaeric protein derived from the fused BCR and ABL genes. This Bcr–Abl protein tyrosine kinase mediates an array of effects on signal transduction pathways affecting cell survival, proliferation, adhesion and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterised by the presence of an excess of myeloid progenitor cells and their mature progeny. This chronic phase of CML is followed, either directly or with an intervening ‘accelerated phase’, by a stage where primitive blast cells predominate (acute transformation). This review discusses the role of Bcr–Abl-mediated signalling events in cellular transformation, genetic instability and disease progression in CML, and describes current developments in CML treatment using a Bcr–Abl inhibitor.

The primary function of cobalamin (Cbl; vitamin B12) is the formation of red blood cells and the maintenance of a healthy nervous system. Before cells can utilise dietary Cbl, the vitamin must undergo cellular transport using two distinct receptor-mediated events. First, dietary Cbl bound to gastric intrinsic factor (IF) is taken up from the apical pole of ileal epithelial cells via a 460 kDa receptor, cubilin, and is transported across the cell bound to another Cbl-binding protein, transcobalamin II (TC II). Second, plasma TC II–Cbl is taken up by cells that need Cbl via the TC II receptor (TC II-R), a 62 kDa protein that is expressed as a functional dimer in cellular plasma membranes. Human Cbl deficiency can develop as a result of acquired or inherited dysfunction in either of these two transmembrane transport events. This review focuses on the biochemical, cellular and molecular aspects of IF and TC II and their cell-surface receptors.

Dietary isoflavones are currently receiving much attention because of their potential role in preventing coronary artery disease and other chronic diseases. Accumulating evidence from cell culture and laboratory animal experiments indicates that isoflavones have the potential to prevent or delay atherogenesis. Suggested mechanisms of action include: a reduction in low-density lipoprotein (LDL) cholesterol and a potential reduction in the susceptibility of the LDL particle to oxidation; (2) an improvement in vascular reactivity; (3) an inhibition of pro-inflammatory cytokines, cell adhesion proteins and nitric oxide (NO) production; and (4) an inhibition of platelet aggregation. These mechanisms are consistent with the epidemiological evidence that a high consumption of isoflavone-rich soy products is associated with a reduced incidence of coronary artery disease. Biological effects of isoflavones are dependent on many factors, including dose consumed, duration of use, protein-binding affinity, and an individual's metabolism or intrinsic oestrogenic state. Further clinical studies are necessary to determine the potential health effects of isoflavones in specific population groups as we currently know little about age-related differences in exposure to these compounds and there are few guidelines on optimal dose for cardiovascular health benefits.

Parkinson's disease (PD) is a common neurodegenerative disorder of the brain and typically presents with a disorder of movement. The core pathological event underlying the condition is the loss of the dopaminergic nigrostriatal pathway with the formation of α-synuclein-positive Lewy bodies. As a result, drugs that target the degenerating dopaminergic network within the brain work well, at least in the early stages of the disease. Unfortunately, with time, these therapies fail and produce their own unique side-effect profile and this, coupled with the more-diffuse pathological and clinical findings in advancing disease, has led to the search for more-effective therapies. In this review, we discuss the emerging new therapies in PD in terms of neuroprotective agents, drugs designed to control symptoms more effectively, and finally curative cell therapies.

The role of the immune system in combating tumour progression has been studied extensively. The two branches of the immune response – humoral and cell-mediated – act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells. The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells. Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance. Attempts are being made to trigger the immune system into an early and efficient response against malignant cells, and various therapeutic modalities are being developed to enhance the strength of the immune response against tumours. This review aims to elucidate the tumouricidal role of various components of the immune system, including macrophages, lymphocytes, dendritic cells and complement.