John Radcliffe Hospital

About: John Radcliffe Hospital is a healthcare organization based out in Oxford, Oxfordshire, United Kingdom. It is known for research contribution in the topics: Population & Antigen. The organization has 14491 authors who have published 23670 publications receiving 1459015 citations.

Neuroinflammation and the generation of neuropathic pain

Abstract: Summary Inflammation is the process by which an organism responds to tissue injury involving both immune cell recruitment and mediator release. Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both. These changes can promote long-term maladaptive plasticity resulting in persistent neuropathic pain. This review aims to provide an overview of inflammatory mechanisms at differing levels of the sensory neuroaxis with a focus on neuropathic pain. We will compare and contrast neuropathic pain states such as traumatic nerve injury which is associated with a vigorous inflammatory response and chemotherapy induced pain in which the inflammatory response is much more modest. Targeting excessive inflammation in neuropathic pain provides potential therapeutic opportunities and we will discuss some of the opportunities but also the clinical challenges in such an approach.

Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies

Abstract: The mammalian skull vault is constructed principally from five bones: the paired frontals and parietals, and the unpaired interparietal. These bones abut at sutures, where most growth of the skull vault takes place. Sutural growth involves maintenance of a population of proliferating osteoprogenitor cells which differentiate into bone matrix-secreting osteoblasts. Sustained function of the sutures as growth centres is essential for continuous expansion of the skull vault to accommodate the growing brain. Craniosynostosis, the premature fusion of the cranial sutures, occurs in 1 in 2500 children and often presents challenging clinical problems. Until a dozen years ago, little was known about the causes of craniosynostosis but the discovery of mutations in the MSX2, FGFR1, FGFR2, FGFR3, TWIST1 and EFNB1 genes in both syndromic and non-syndromic cases has led to considerable insights into the aetiology, classification and developmental pathology of these disorders. Investigations of the biological roles of these genes in cranial development and growth have been carried out in normal and mutant mice, elucidating their individual and interdependent roles in normal sutures and in sutures undergoing synostosis. Mouse studies have also revealed a significant correspondence between the neural crest–mesoderm boundary in the early embryonic head and the position of cranial sutures, suggesting roles for tissue interaction in suture formation, including initiation of the signalling system that characterizes the functionally active suture.

New insights into the mobilization and phagocytic activity of dendritic cells.

Abstract: A study published in this issue of The Journal of Experimental Medicine, sheds new light on the behavior and functions of dendritic cells (DC) which play a pivotal role in initiation of T and T-dependent immune responses (1). The study is important in at least three respects: first, it provides information on recruitment of DC progenitors to a non-lymphoid tissue, the liver; second, it provides evidence that DC have transient phagocytic activity for particulates in vivo, a prerequisite for induction of immune responses against bacteria for example; and third, it defines a migration pathway for DC, that have acquired particulates from the blood, from the liver to draining nodes. To put this paper (1) into context it is necessary to summarize the general consensus of understanding about the DC lineage that has emerged over the past decade or so. DC progenitors that originate from the bone marrow of adult mammals enter the blood and seed non-lymphoid tissues, where they develop into a stage of DC (sometimes referred to as immature DC) with optimal capabilities for antigen uptake and processing, MHC production, and the formation of foreign peptide-MHC complexes (\"processing\" DC). These cells are localized in epitheha, such as skin epidermis, gut, genito-urinary tract, and the lung and airways, and in the interstitial spaces of many solid organs such as heart and kidney. Inflammatory mediators (cytokines and other agents) then promote their maturation and migration out of non-lymphoid tissues into blood and/or afferent lymph. These migratory cells enter secondary lymphoid tissues where they express newly acquired capabilities for the initiation of primary T and T-dependent immune responses, at least in part due to their expression of costimulatory molecules and synthesis of certain cytokines such as IL-12 (\"presenting\" DC, sometimes referred to as mature DC). Migratory DC, travelling between non-lymphoid and secondary lymphoid tissues, are generally considered to be undergoing \"maturation\" from the processing to presenting stages, although maturation is likely to be initiated within non-lymphoid tissues and to continue within secondary lymphoid tissues. At the outset, it is therefore convenient to define four stages of the DC lineage in distinct anatomical compartments: DC progenitors in bone marrow and blood; immature DC at the processing stage in peripheral non-lymphoid organs; migratory DC in the process of maturation in afferent lymph and blood; and mature DC at the presenting stage in secondary lymphoid tissues (2-4). Arguably this view is an over-simplification. For example, DC progenitors may enter secondary lymphoid tissues directly; some DC in non-lymphoid tissues may possess a degree of costimulatory activity; some DC in lymphoid tissues may be capable of antigen uptake and processing to some extent; and DC in thymus may play a role in the induction of T cell tolerance to self peptide-MHC complexes. Nevertheless, it provides a useful framework for understanding how, where, and when DC regulate the induction of primary immune responses. It is also important to add that once antigen-specific T cells have been activated by DC, the activated T cells appear not to require the specialized costimulatory signals that are delivered by DC, and may respond to other types of antigen-presenting cell expressing the peptide-MHC complexes for which they are specific (2, 3). DCProgenitors. A major advance over the past few years has been the ability to grow DC from bone marrow and blood progenitors and to control production of different stages of the lineage in vitro. For example, development of immature human DC is promoted by culture of bone marrow or blood progenitors in the presence of GMCSF and IL-4 (5, 6), and further maturation can be induced by subsequent exposure to TNF-ot or CD40 ligand, or to other agents such as bacterial lipopolysaccharide (LPS) (7). Inclusion of stem cell factor (c-kit ligand) increases cell yields and permits discrete colonies of DC to be grown in semi-solid culture systems (8). Nevertheless the identification of bona fide DC progenitors remains difficult: DC may share a committed stem cell with monocytes and neutrophils (9); or with T cells, B cells and NK cells (10); or indeed they may differentiate from monocytes. However, it is possible to generate mouse DC from presumptive liver progenitors cultured in the presence of GM-CSF, further maturation being promoted by the presence of type-1 collagen in vitro (11); these progenitors may be capable of seeding secondary lymphoid tissues, and possibly some non-lymphoid tissues, following liver allografting in vivo (12). What stimuli recruit DC progenitors into the tissues? Regarding epithelia, there is evidence that intradermal administration of GM-CSF leads to an increase in numbers of DC within the dermis of human skin, which may be the precursors to epidermal Langerhans cells (LC, the DC of skin epidermis) (13). In addition, GM-CSF produced by normal and inflamed tissues, and some carcinomas, within

Streptococcus suis: an emerging human pathogen.

Abstract: Streptococcus suis infection is acquired through exposure to contaminated pigs or pig meat. Over the past few years, the number of reported S. suis infections in humans has increased significantly, with most cases originating in Southeast Asia, where there is a high density of pigs. Increased awareness, improved diagnostics, and the occurrence of outbreaks have contributed to this increase. Meningitis and sepsis are the most common clinical manifestations of S. suis infection; hearing loss is a frequent complication. In this article, we provide an overview of the emergence and clinical manifestations of S. suis infection.

Potassium channel antibodies in two patients with reversible limbic encephalitis.

Abstract: Limbic encephalitis (LE) is often associated with lung, thymic, or testicular tumours and antibodies to Hu, CV2, or Ma2 (Ta) antigens. In these cases, it generally has a poor prognosis. Here we describe two patients with symptoms of LE, negative for typical paraneoplastic antibodies, in whom antibodies to voltage-gated potassium channels (VGKC) were detected retrospectively in serial serum samples. Patient 1 had a thymoma recurrence, but in patient 2 no tumour has been detected in the years following presentation. Plasma exchange was effective in reducing VGKC antibody levels, with substantial improvement in mental symptoms in patient 1. In patient 2, the VGKC antibodies fell spontaneously over two years, with almost complete recovery of mental function. Although neither patient had obvious neuromyotonia at presentation, both showed excessive secretions. We suggest that patients with limbic symptoms and excessive secretions should be tested for VGKC antibodies, and, if they are present, prompt and effective immunosuppressive treatment should be considered.