Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection

The CD8+ T cell response to Epstein-Barr virus (EBV) is well characterized. Much less is known about the evolution of the CD4+ T cell response. Here we show that EBV stimulates a primary burst of effector CD4+ T cells and this is followed by a period of down-regulation. A small population of EBV-specific effector CD4+ T cells survives during the lifelong persistent phase of infection. The EBV-specific effector CD4+ T cells accumulate within a CD27+ CD28+ differentiation compartment during primary infection and remain enriched within this compartment throughout the persistent phase of infection. Analysis of CD4+ T cell responses to individual epitopes from EBV latent and lytic cycle proteins confirms the observation that the majority of the effector cells express both CD27 and CD28, although CD4+ T cells specific for lytic cycle antigens have a greater tendency to express CD45RA than those specific for the latent antigens. In clear contrast, effector CD4+ T cells specific for cytomegalovirus (CMV) accumulate within the CD27- CD28+ and CD27- CD28- compartments. There are striking parallels in terms of the differentiation of CD8+ T cells specific for EBV and CMV. The results challenge current ideas on the definition of memory subsets.     

Staff Stress and Morale in Community‐Based Settings for People with Intellectual Disabilities and Challenging Behaviour: A Brief Report

Background There are no studies that have compared outcomes for staff in different types of supported accommodation for people with intellectual disabilities and challenging behaviour. This study looked at stress, morale and intended job turnover in staff in two types of community‐based residential supports: non‐congregate settings where the minority of residents have challenging behaviour; and congregate settings where the majority of residents have challenging behaviour. Materials and methods A self‐completion survey questionnaire was used to collect information on the basic characteristics of staff, levels of staff stress, job satisfaction and propensity to leave their employment. Results One hundred and fifty‐seven questionnaires were returned from staff, the majority of whom were on fixed‐term contracts. Congregate settings were not associated with higher levels of stress as might be assumed. Overall, over a quarter of staff reached criterion on the General Health Questionnaire‐12 for experiencing emotional distress, and over a third were likely to actively seek new employment in the next year. The greatest perceived sources of stress were lack of resources and lack of staff support. The lowest level of satisfaction was with the rate of pay. Those in non‐congregate settings reported greater perceived stress because of lack of procedures to deal with challenging behaviour. Conclusions High levels of intended staff turnover may be more due to job insecurity and lack of support than service user challenging behaviour. Employers seeking to reduce turnover should pay attention to basic pay and conditions, as well as staff training in appropriate methods for dealing with challenging behaviour.     

CD8(+) T-cell selection, function, and death in the primary immune response in vivo

The primary immune response to Epstein Barr virus (EBV) is characterized by striking proliferation of EBV-specific CD8(+) T cells. In this study we have investigated the clonal composition and functional properties of the cells mediating this primary response and have analyzed the mechanisms that control the downregulation of the primary response and the selection of memory cells. We show that massively expanded T-cell clones often dominate the primary antigen-specific T-cell response. Despite the enormous extent of expansion, the virus-specific T cells express high levels of intracellular perforin and are potently cytotoxic. They are, however, functionally heterogeneous in their ability to secrete proinflammatory cytokines, with subpopulations of the antigen-specific T cells being hyporesponsive. The primary response is closely regulated, and the majority of cells are programmed to die via a cytokine-rescuable pathway, leaving only small populations of memory T cells surviving. Comparison of the clonal composition of primary and memory responses in vivo shows that the clones that dominate the primary response are relatively heavily culled during the downregulation of the primary response and the establishment of T-cell memory.     

α- andβ-mannosidoses

Summary Clinical, pathological and biochemical findings in the mannosidoses are described. Family studies showed granulocyte-rich white cell fractions to be the tissue of choice for carrier detection in-mannosidosis. Metabolic labelling studies using [³H] mannose demonstrated accumulation of Man1-4GlcNAc in cultured skin fibroblasts from a patient with this condition. Alternative methods of egress from lysosomes were suggested for this compound by its secretion into culture medium and apparent reduction of storage with time in cultures.-mannosidase deficient goats are not thought to be a true animal model of the human condition, as although they showed a similar enzyme deficiency, the clinical presentation is much more severe and the major storage material (Man1-4GlcNAc1-4GlcNAc) is different.     

Synthesis of four racemic nicotine isotopomers doubly labelled with stable isotope

Four racemic nicotine isotopomers, doubly labelled with stable isotope, were prepared for use in studies of plant metabolism. First, starting from halogeno nicotinates, one deuterium was introduced into the pyridine moiety by reductive dehalogenation with zinc, and choosing deuterated acetic acid as the acidic medium. Pyridine ²H‐labelled nornicotine derivatives were then formed in two reaction steps, a condensation reaction with N‐vinylpyrrolidinone followed by catalytic hydrogenation. The deuteromethylation of these monodeuterated nornicotines was achieved by reduction of the corresponding ethyl carbamates with deuterated lithium aluminium hydride. The four regioisotopomers obtained were at the least 90% labelled on each site, sufficient for the metabolic studies envisaged. Copyright © 2009 John Wiley & Sons, Ltd.     

Feasibility of image registration and intensity-modulated radiotherapy planning with hyperpolarized helium-3 magnetic resonance imaging for non-small-cell lung cancer

PURPOSE: To demonstrate the feasibility of registering hyperpolarized helium-3 magnetic resonance images ((3)He-MRI) to X-ray computed tomography (CT) for functionally weighted intensity-modulated radiotherapy (IMRT) planning. METHODS AND MATERIALS: Six patients with non-small-cell lung cancer underwent (3)He ventilation MRI, which was fused with radiotherapy planning CT using rigid registration. Registration accuracy was assessed using an overlap coefficient, calculated as the proportion of the segmented (3)He-MR volume (V(MRI)) that intersects the segmented CT lung volume expressed as a percentage of V(MRI). For each patient, an IMRT plan that minimized the volume of total lung receiving a dose > or = 20 Gy (V(20)) was compared with a plan that minimized the V(20) to well-ventilated lung defined by the registered (3)He-MRI. RESULTS: The (3)He-MRI and CT were registered with sufficient accuracy to enable functionally guided IMRT planning (median overlap, 89%; range, 72-97%). In comparison with the total lung IMRT plans, IMRT constrained with (3)He-MRI reduced the V(20) not only for the well-ventilated lung (median reduction, 3.1%; range, 0.4-5.1%; p = 0.028) but also for the total lung volume (median reduction, 1.6%; range, 0.2-3.7%; p = 0.028). CONCLUSIONS: Statistically significant improvements to IMRT plans are possible using functional information provided by (3)He-MRI that has been registered to radiotherapy planning CT.