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.

Communication between Multiple Drug Binding Sites on P-glycoprotein

Abstract: P-glycoprotein, a member of the ATP-binding cassette transporter family, is able to confer resistance on tumors against a large number of functionally and chemically distinct cytotoxic compounds. Several recent investigations suggest that P-glycoprotein contains multiple drug binding sites rather than a single site of broad substrate specificity. In the present study, radioligand-binding techniques were used to directly characterize drug interaction sites on P-glycoprotein and how these multiple sites interact. The drugs used were classified as either 1) substrates, which are known to be transported by P-glycoprotein (e.g., vinblastine) or 2) modulators, which alter P-glycoprotein function but are not themselves transported by the protein (e.g., XR9576). Drug interactions with P-glycoprotein were either competitive, at a common site, or noncompetitive, and therefore at distinct sites. Based on these data, we can assign a minimum of four drug binding sites on P-glycoprotein. These sites fall into two categories: transport, at which translocation of drug across the membrane can occur, and regulatory sites, which modify P-glycoprotein function. Intriguingly, however, some modulators interact with P-glycoprotein at a transport site rather than a regulatory site. The pharmacological data also demonstrate that both transport and regulatory sites are able to switch between high- and low-affinity conformations. The multiple sites on P-glycoprotein display complex allosteric interactions through which interaction of drug at one site switches other sites between high- or low-affinity conformations. The data are discussed in terms of a model for the mechanism of transport by P-glycoprotein.

Association between atopy and variants of the β subunit of the high–affinity immunoglobulin E receptor

Abstract: The β–subunit of the high–affinity IgE receptor (FceRI–β) on chromosome 11 is maternally linked to atopy, the state of enhanced IgE responsiveness underlying allergic asthma and rhinitis. We have identified a common variant of FceRI–β, lle181Leu within the 4th transmembrane domain. Leu181 shows significant association with positive IgE responses in a random patient sample. Amongst 60 unrelated nuclear families with allergic asthmatic probands, Leu181 is identified in 10 (17%), is maternally inherited in each, and shows a strong association with atopy. Our data indicate that FceRI–β, subject to maternal modification, may be the atopy–causing locus on chromosome 11q.

Clinical and Psychological Course of Diabetes From Adolescence to Young Adulthood: A longitudinal cohort study

Abstract: OBJECTIVE —To determine the clinical and psychological course of diabetes through adolescence and the relationship with glycemic control in young adulthood. RESEARCH DESIGN AND METHODS —A longitudinal cohort study of adolescents recruited from the register of the outpatient pediatric diabetes clinic. A total of 76 individuals (43 male patients, 33 female patients) aged 11–18 years completed baseline assessments, and 65 individuals (86%) were reinterviewed as young adults (20–28 years of age). Longitudinal assessments were made of glycemic control (HbA 1c ), weight gain (BMI), and development of complications. Adolescents completed self-report questionnaires to assess emotional and behavioral problems as well as self-esteem. As young adults, psychological state was assessed by the Revised Clinical Interview Schedule and the self-report Brief Symptom Inventory. RESULTS —Mean HbA 1c levels peaked in late adolescence and were worse in female participants (average 11.1% at 18–19 years of age). The proportion of individuals who were overweight (BMI >25.0 kg/m 2 ) increased during the 8-year period from 21 to 54% in female patients and from 2 to 28% in male patients. Serious diabetes-related events included death in one patient and cognitive impairment in two patients. Individuals in whom diabetic complications developed (25% of male patients and 38% of female patients) had significantly higher mean HbA 1c levels than those without complications (difference 1.9%, 95% CI 1.1–2.7, P 1c during the subsequent 8 years (β = 0.15, SEM (β) 0.04, P CONCLUSIONS —The outcome for this cohort was generally poor. Behavioral problems in adolescence seem to be important in influencing later glycemic control.

Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells

Abstract: Background Activation of the group 2 innate lymphoid cell (ILC2) population leads to production of the classical type 2 cytokines, thus promoting type 2 immunity. Chemoattractant receptor-homologous molecule expressed on T H2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2), is expressed by human ILC2s. However, the function of CRTH2 in these cells is unclear. Objectives We sought to determine the role of PGD2 and CRTH2 in human ILC2s and compare it with that of the established ILC2 activators IL-25 and IL-33. Methods The effects of PGD 2, IL-25, and IL-33 on the cell migration, cytokine production, gene regulation, and receptor expression of ILC2s were measured with chemotaxis, ELISA, Luminex, flow cytometry, quantitative RT-PCR, and QuantiGene assays. The effects of PGD2 under physiologic conditions were evaluated by using the supernatant from activated mast cells. Results PGD2 binding to CRTH2 induced ILC2 migration and production of type 2 cytokines and many other cytokines. ILC2 activation through CRTH2 also upregulated the expression of IL-33 and IL-25 receptor subunits (ST2 and IL-17RA). The effects of PGD 2 on ILC2s could be mimicked by the supernatant from activated human mast cells and inhibited by a CRTH2 antagonist. Conclusions PGD2 is an important and potent activator of ILC2s through CRTH2 mediating strong proallergic inflammatory responses. Through IgE-mediated mast cell degranulation, these innate cells can also contribute to adaptive type 2 immunity; thus CRTH2 bridges the innate and adaptive pathways in human ILC2s. © 2013 American Academy of Allergy, Asthma & Immunology.