CD20 and CD19 targeted vectors induce minimal activation of resting B lymphocytes

B lymphocytes are an important cell population of the immune system. However, until recently it was not possible to transduce resting B lymphocytes with retro- or lentiviral vectors, making them unsusceptible for genetic manipulations by these vectors. Lately, we demonstrated that lentiviral vectors pseudotyped with modified measles virus (MV) glycoproteins hemagglutinin, responsible for receptor recognition, and fusion protein were able to overcome this transduction block. They use either the natural MV receptors, CD46 and signaling lymphocyte activation molecule (SLAM), for cell entry (MV-LV) or the vector particles were further modified to selectively enter via the CD20 molecule, which is exclusively expressed on B lymphocytes (CD20-LV). It has been shown previously that transduction by MV-LV does not induce B lymphocyte activation. However, if this is also true for CD20-LV is still unknown. Here, we generated a vector specific for another B lymphocyte marker, CD19, and compared its ability to transduce resting B lymphocytes with CD20-LV. The vector (CD19ds-LV) was able to stably transduce unstimulated B lymphocytes, albeit with a reduced efficiency of about 10% compared to CD20-LV, which transduced about 30% of the cells. Since CD20 as well as CD19 are closely linked to the B lymphocyte activation pathway, we investigated if engagement of CD20 or CD19 molecules by the vector particles induces activating stimuli in resting B lymphocytes. Although, activation of B lymphocytes often involves calcium influx, we did not detect elevated calcium levels. However, the activation marker CD71 was substantially up-regulated upon CD20-LV transduction and most importantly, B lymphocytes transduced with CD20-LV or CD19ds-LV entered the G1b phase of cell cycle, whereas untransduced or MV-LV transduced B lymphocytes remained in G0. Hence, CD20 and CD19 targeting vectors induce activating stimuli in resting B lymphocytes, which most likely renders them susceptible for lentiviral vector transduction

Bridging the gap between the economic evaluation literature and daily practice in occupational health: a qualitative study among decision-makers in the healthcare sector

Background: Continued improvements in occupational health can only be ensured if decisions regarding the implementation and continuation of occupational health and safety interventions (OHS interventions) are based on the best available evidence. To ensure that this is the case, scientific evidence should meet the needs of decision-makers. As a first step in bridging the gap between the economic evaluation literature and daily practice in occupational health, this study aimed to provide insight into the occupational health decision-making process and information needs of decision-makers.Methods: An exploratory qualitative study was conducted with a purposeful sample of occupational health decision-makers in the Ontario healthcare sector. Eighteen in-depth interviews were conducted to explore the process by which occupational health decisions are made and the importance given to the financial implications of OHS interventions. Twenty-five structured telephone interviews were conducted to explore the sources of information used during the decision-making process, and decision-makers' knowledge on economic evaluation methods. In-depth interview data were analyzed according to the constant comparative method. For the structured telephone interviews, summary statistics were prepared.Results: The occupational health decision-making process generally consists of three stages: initiation stage, establishing the need for an intervention; pre-implementation stage, developing an intervention and its business case in order to receive senior management approval; and implementation and evaluation stage, implementing and evaluating an intervention. During this process, information on the financial implications of OHS interventions was found to be of great importance, especially the employer's costs and benefits. However, scientific evidence was rarely consulted, sound ex-post program evaluations were hardly ever performed, and there seemed to be a need to advance the economic evaluation skill set of decision-makers.Conclusions: Financial information is particularly important at the front end of implementation decisions, and can be a key deciding factor of whether to go forward with a new OHS intervention. In addition, it appears that current practice in occupational health in the healthcare sector is not solidly grounded in evidence-based decision-making and strategies should be developed to improve this. © 2013 van Dongen et al.; licensee BioMed Central Ltd

Investigating the Willingness to Pay for a Contributory National Health Insurance Scheme in Saudi Arabia:A Cross-sectional Stated Preference Approach

Background: The Saudi Healthcare System is universal, financed entirely from government revenue principally derived from oil, and is ‘free at the point of delivery’ (non-contributory). However, this system is unlikely to be sustainable in the medium to long term. This study investigates the feasibility and acceptability of healthcare financing reform by examining households’ willingness to pay (WTP) for a contributory national health insurance scheme. Methods: Using the contingent valuation method, a pre-tested interviewer-administered questionnaire was used to collect data from 1187 heads of household in Jeddah province over a 5-month period. Multi-stage sampling was employed to select the study sample. Using a double-bounded dichotomous choice with the follow-up elicitation method, respondents were asked to state their WTP for a hypothetical contributory national health insurance scheme. Tobit regression analysis was used to examine the factors associated with WTP and assess the construct validity of elicited WTP. Results: Over two-thirds (69.6%) indicated that they were willing to participate in and pay for a contributory national health insurance scheme. The mean WTP was 50 Saudi Riyal (US$13.33) per household member per month. Tobit regression analysis showed that household size, satisfaction with the quality of public healthcare services, perceptions about financing healthcare, education and income were the main determinants of WTP. Conclusions: This study demonstrates a theoretically valid WTP for a contributory national health insurance scheme by Saudi people. The research shows that willingness to participate in and pay for a contributory national health insurance scheme depends on participant characteristics. Identifying and understanding the main influencing factors associated with WTP are important to help facilitate establishing and implementing the national health insurance scheme. The results could assist policy-makers to develop and set insurance premiums, thus providing an additional source of healthcare financing

Proteomic Analysis of S-Acylated Proteins in Human B Cells Reveals Palmitoylation of the Immune Regulators CD20 and CD23

S-palmitoylation is a reversible post-translational modification important for controlling the membrane targeting and function of numerous membrane proteins with diverse roles in signalling, scaffolding, and trafficking. We sought to identify novel palmitoylated proteins in B lymphocytes using acyl-biotin exchange chemistry, coupled with differential analysis by liquid-chromatography tandem mass spectrometry. In total, we identified 57 novel palmitoylated protein candidates from human EBV-transformed lymphoid cells. Two of them, namely CD20 and CD23 (low affinity immunoglobulin epsilon Fc receptor), are immune regulators that are effective/potential therapeutic targets for haematological malignancies, autoimmune diseases and allergic disorders. Palmitoylation of CD20 and CD23 was confirmed by heterologous expression of alanine mutants coupled with bioorthogonal metabolic labeling. This study demonstrates a new subset of palmitoylated proteins in B cells, illustrating the ubiquitous role of protein palmitoylation in immune regulation

Birth Weight and Adult IQ, but Not Anxious-Depressive Psychopathology, Are Associated with Cortical Surface Area: A Study in Twins

BACKGROUND: Previous research suggests that low birth weight (BW) induces reduced brain cortical surface area (SA) which would persist until at least early adulthood. Moreover, low BW has been linked to psychiatric disorders such as depression and psychological distress, and to altered neurocognitive profiles. AIMS: We present novel findings obtained by analysing high-resolution structural MRI scans of 48 twins; specifically, we aimed: i) to test the BW-SA association in a middle-aged adult sample; and ii) to assess whether either depression/anxiety disorders or intellectual quotient (IQ) influence the BW-SA link, using a monozygotic (MZ) twin design to separate environmental and genetic effects. RESULTS: Both lower BW and decreased IQ were associated with smaller total and regional cortical SA in adulthood. Within a twin pair, lower BW was related to smaller total cortical and regional SA. In contrast, MZ twin differences in SA were not related to differences in either IQ or depression/anxiety disorders. CONCLUSION: The present study supports findings indicating that i) BW has a long-lasting effect on cortical SA, where some familial and environmental influences alter both foetal growth and brain morphology; ii) uniquely environmental factors affecting BW also alter SA; iii) higher IQ correlates with larger SA; and iv) these effects are not modified by internalizing psychopathology.This work was supported by the Spanish SAF2008-05674, European Twins Study Network on Schizophrenia Research Training Network (grant number EUTwinsS; MRTN-CT-2006-035987), the Catalan 2014SGR1636 and the PIM2010-ERN- 00642 in frame of ERA-NET NEURON. A. Córdova- Palomera was funded by The National Council for Science and Technology (CONACyT, Mexico). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Pattern of neural responses to verbal fluency shows diagnostic specificity for schizophrenia and bipolar disorder

<p>Abstract</p> <p>Background</p> <p>Impairments in executive function and language processing are characteristic of both schizophrenia and bipolar disorder. Their functional neuroanatomy demonstrate features that are shared as well as specific to each disorder. Determining the distinct pattern of neural responses in schizophrenia and bipolar disorder may provide biomarkers for their diagnoses.</p> <p>Methods</p> <p>104 participants underwent functional magnetic resonance imaging (fMRI) scans while performing a phonological verbal fluency task. Subjects were 32 patients with schizophrenia in remission, 32 patients with bipolar disorder in an euthymic state, and 40 healthy volunteers. Neural responses to verbal fluency were examined in each group, and the diagnostic potential of the pattern of the neural responses was assessed with machine learning analysis.</p> <p>Results</p> <p>During the verbal fluency task, both patient groups showed increased activation in the anterior cingulate, left dorsolateral prefrontal cortex and right putamen as compared to healthy controls, as well as reduced deactivation of precuneus and posterior cingulate. The magnitude of activation was greatest in patients with schizophrenia, followed by patients with bipolar disorder and then healthy individuals. Additional recruitment in the right inferior frontal and right dorsolateral prefrontal cortices was observed in schizophrenia relative to both bipolar disorder and healthy subjects. The pattern of neural responses correctly identified individual patients with schizophrenia with an accuracy of 92%, and those with bipolar disorder with an accuracy of 79% in which mis-classification was typically of bipolar subjects as healthy controls.</p> <p>Conclusions</p> <p>In summary, both schizophrenia and bipolar disorder are associated with altered function in prefrontal, striatal and default mode networks, but the magnitude of this dysfunction is particularly marked in schizophrenia. The pattern of response to verbal fluency is highly diagnostic for schizophrenia and distinct from bipolar disorder. Pattern classification of functional MRI measurements of language processing is a potential diagnostic marker of schizophrenia.</p

Thomas Graham Brown (1882–1965): Behind the Scenes at the Cardiff Institute of Physiology

Thomas Graham Brown undertook seminal experiments on the neural control of locomotion between 1910 and 1915. Although elected to the Royal Society in 1927, his locomotion research was largely ignored until the 1960s when it was championed and extended by the distinguished neuroscientist, Anders Lundberg. Puzzlingly, Graham Brown's published research stopped in the 1920s and he became renowned as a mountaineer. In this article, we review his life and multifaceted career, including his active neurological service in WWI. We outline events behind the scenes during his tenure at Cardiff's Institute of Physiology in Wales, UK, including an interview with his technician, Terrence J. Surman, who worked in this institute for over half a century

Fixation durations in scene viewing:Modeling the effects of local image features, oculomotor parameters, and task

Scene perception requires the orchestration of image- and task-related processes with oculomotor constraints. The present study was designed to investigate how these factors influence how long the eyes remain fixated on a given location. Linear mixed models (LMMs) were used to test whether local image statistics (including luminance, luminance contrast, edge density, visual clutter, and the number of homogeneous segments), calculated for 1° circular regions around fixation locations, modulate fixation durations, and how these effects depend on task-related control. Fixation durations and locations were recorded from 72 participants, each viewing 135 scenes under three different viewing instructions (memorization, preference judgment, and search). Along with the image-related predictors, the LMMs simultaneously considered a number of oculomotor and spatiotemporal covariates, including the amplitudes of the previous and next saccades, and viewing time. As a key finding, the local image features around the current fixation predicted this fixation’s duration. For instance, greater luminance was associated with shorter fixation durations. Such immediacy effects were found for all three viewing tasks. Moreover, in the memorization and preference tasks, some evidence for successor effects emerged, such that some image characteristics of the upcoming location influenced how long the eyes stayed at the current location. In contrast, in the search task, scene processing was not distributed across fixation durations within the visual span. The LMM-based framework of analysis, applied to the control of fixation durations in scenes, suggests important constraints for models of scene perception and search, and for visual attention in general

Breast cancer in young women

Although uncommon, breast cancer in young women is worthy of special attention due to the unique and complex issues that are raised. This article reviews specific challenges associated with the care of younger breast cancer patients, which include fertility preservation, management of inherited breast cancer syndromes, maintenance of bone health, secondary prevention, and attention to psychosocial issues