Effect of vitamin D on Epstein-Barr (EBV)-specific CD8+T cells in patients with early multiple sclerosis (MS)

Background: Infection with EBV and a lack in vitamin D may be important environmental triggers of MS. 1,25-(OH)2D3 mediates a shift of antigen presenting cells (APC) and CD4+ T cells to a less inflammatory profile. Although CD8+ T cells do express the vitamin D receptor, a direct effect of 1,25(OH)2D3 on these cells has not been demonstrated until now. Since CD8+ T cells are important immune mediators of the inflammatory response in MS, we examined whether vitamin D directly affects the CD8+ T cell response, and more specifically if it modulates the EBV-specific CD8+ T cell response. Material and Methods: To explore whether the vitamin D status may influence the pattern of the EBV-specific CD8+ T cell response, PBMC of 10 patients with early MS and 10 healthy controls (HC) were stimulated with a pool of immunodominant 8-10 mer peptide epitopes known to elicit CD8+ T cell responses. PBMC were stimulated with this EBV CD8 peptide pool, medium (negative control) or anti- CD3/anti-CD28 beads (positive control). The following assays were performed: ELISPOT to assess the secretion of IFN-gamma by T cells in general; cytometric beads array (CBA) and ELISA to determine whichcytokines were released by EBV-specific CD8+ T cells after six days of culture; and intracellular cytokine staining assay to determine by which subtype of T cells secreted given cytokines. To examine whether vitamin D could directly modulate CD8+ T cell immune responses, we depleted CD4+ T cells using negative selection. Results: We found that pre-treatment of vitamin D had an antiinflammatory action on both EBV-specific CD8+ T cells and on CD3/ CD28-stimulated T cells: secretion of pro-inflammatory cytokines (IFNgamma and TNF-alpha) was decreased, whereas secretion of antiinflammatory cytokines (IL-5 and TGF-beta) was increased. At baseline, CD8+ T cells of early MS patients showed a higher secretion of TNFalpha and lower secretion of IL-5. Addition of vitamin D did not restore the same levels of both cytokines as compared to HC. Vitamin D-pretreated CD8+T cells exhibited a decreased secretion of IFN-gamma and TNF-alpha, even after depletion of CD4+ T cells from culture. Conclusion: Vitamin D has a direct anti-inflammatory effect on CD8+ T cells independently from CD4+ T cells. CD8+ T cells of patients with earlyMS are less responsive to the inflammatory effect of vitamin D than HC, pointing toward an intrinsic dysregulation of CD8+ T cells. The modulation of EBV-specific CD8+T cells by vitaminDsuggests that there may be interplay between these twomajor environmental factors of MS. This study was supported by a grant from the Swiss National Foundation (PP00P3-124893), and by an unrestricted research grant from Bayer to RDP.

Indirect effects of peri-and postnatal choline treatment on place-learning abilities in rat.

This work was aimed at analyzing the effects of perinatal choline supplementation on the development of spatial abilities and upon adult performance. Choline supplementation (3.5 g/L in 0.02 M saccharin solution in tap water) was maintained for two weeks before birth and for up to four weeks postnatally. Additional supplementation was maintained from the fifth to the tenth week postnatally. Spatial-learning capacities were studied at the ages of 26, 65, or 80 days in a circular swimming pool (Morris place-navigation task) and at the age of 7 months in a homing arena. Treatment effects were found in both juvenile and adult rats, and thus persisted for several months after the cessation of the supplementation. The choline supplementation improved the performance in the water maze in a very selective manner. The most consistent effect was a reduction in the latency to reach a cued platform at a fixed position in space, whereas the improvement was limited when the platform was invisible and had to be located relative to distant cues only. However, after removal of the goal cue, the treated rats showed a better retention of the training position than did the control rats. A similar effect was observed in a dry-land task conducted in the homing arena. The choline supplementation thus induced a significant improvement of spatial memory. But since this effect was only evident following training with a salient cue, it might be regarded as an indirect effect promoted by an optimal combination of cue guidance with a place strategy.

Do Financial Incentives Affect Firms' Demand For Disabled Workers?

A number of OECD countries aim to encourage work integration of disabled persons using quota policies. For instance, Austrian firms must provide at least one job to a disabled worker per 25 nondisabled workers and are subject to a tax if they do not. This "threshold design" provides causal estimates of the noncompliance tax on disabled employment if firms do not manipulate nondisabled employment; a lower and upper bound on the causal effect can be constructed if they do. Results indicate that firms with 25 nondisabled workers employ about 0.04 (or 12%) more disabled workers than without the tax; firms do manipulate employment of nondisabled workers but the lower bound on the employment effect of the quota remains positive; employment effects are stronger in low-wage firms than in high-wage firms; and firms subject to the quota of two disabled workers or more hire 0.08 more disabled workers per additional quota job. Moreover, increasing the noncompliance tax increases excess disabled employment, whereas paying a bonus to overcomplying firms slightly dampens the employment effects of the tax.

Beyond contact-based transmission networks: the role of spatial coincidence.

Animal societies rely on interactions between group members to effectively communicate and coordinate their actions. To date, the transmission properties of interaction networks formed by direct physical contacts have been extensively studied for many animal societies and in all cases found to inhibit spreading. Such direct interactions do not, however, represent the only viable pathways. When spreading agents can persist in the environment, indirect transmission via 'same-place, different-time' spatial coincidences becomes possible. Previous studies have neglected these indirect pathways and their role in transmission. Here, we use rock ant colonies, a model social species whose flat nest geometry, coupled with individually tagged workers, allowed us to build temporally and spatially explicit interaction networks in which edges represent either direct physical contacts or indirect spatial coincidences. We show how the addition of indirect pathways allows the network to enhance or inhibit the spreading of different types of agent. This dual-functionality arises from an interplay between the interaction-strength distribution generated by the ants' movement and environmental decay characteristics of the spreading agent. These findings offer a general mechanism for understanding how interaction patterns might be tuned in animal societies to control the simultaneous transmission of harmful and beneficial agents.

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The aim of this chapter is to provide an understanding of retirement adjustment by specifically focusing on meaning in life for retirees and meaningful work for older workers who are close to retirement. After a first outline of global issues of aging and work, we approach transition to retirement from the standpoint of sustainable careers within its main dimensions of continuity and importance of personal agency. Next, we review and synthesize literature on meaningful work and meaning in life, distinguishing three levels that constitute meaningful work and five dimensions of meaning in life. To illustrate our points, we present quotations from semi-structured interviews realized with Swiss older workers who were going to retire within a few months. Then, we describe ways to promote meaningful work for older workers and how to create a new meaning or to pursue a previous meaning as a retiree. Finally, we suggest ways individuals, organizations, and career counselors can facilitate a meaningful transition to retirement.

Associations of short-term particle and noise exposures with markers of cardiovascular and respiratory health among highway maintenance workers

BACKGROUND: Highway maintenance workers are constantly and simultaneously exposed to traffic-related particle and noise emissions, and both have been linked to increased cardiovascular morbidity and mortality in population-based epidemiology studies. OBJECTIVES: We aimed to investigate short-term health effects related to particle and noise exposure. METHODS: We monitored 18 maintenance workers, during as many as five 24-hour periods from a total of 50 observation days. We measured their exposure to fine particulate matter (PM2.5), ultrafine particles, noise, and the cardiopulmonary health endpoints: blood pressure, pro-inflammatory and pro-thrombotic markers in the blood, lung function and fractional exhaled nitric oxide (FeNO) measured approximately 15 hours post-work. Heart rate variability was assessed during a sleep period approximately 10 hours post-work. RESULTS: PM2.5 exposure was significantly associated with C-reactive protein and serum amyloid A, and negatively associated with tumor necrosis factor α. None of the particle metrics were significantly associated with von Willebrand factor or tissue factor expression. PM2.5 and work noise were associated with markers of increased heart rate variability, and with increased HF and LF power. Systolic and diastolic blood pressure on the following morning were significantly associated with noise exposure after work, and non-significantly associated with PM2.5. We observed no significant associations between any of the exposures and lung function or FeNO. CONCLUSIONS: Our findings suggest that exposure to particles and noise during highway maintenance work might pose a cardiovascular health risk. Actions to reduce these exposures could lead to better health for this population of workers.

Compartmentalization in membrane rafts defines a pool of N-cadherin associated with catenins and not engaged in cell-cell junctions in melanoma cells.

Melanoma progression is associated with changes in adhesion receptor expression, in particular upregulation of N-cadherin which promotes melanoma cell survival and invasion. Plasma membrane lipid rafts contribute to the compartmentalization of signaling complexes thereby regulating their function, but how they may affect the properties of adhesion molecules remains elusive. In this study, we addressed the question whether lipid rafts in melanoma cells may contribute to the compartmentalization of N-cadherin. We show that a fraction of N-cadherin in a complex with catenins is associated with cholesterol/sphingolipid-rich membrane microdomains in aggressive melanoma cells in vitro and experimental melanomas in vivo. Partitioning of N-cadherin in membrane rafts is not modulated by growth factors and signaling pathways relevant to melanoma progression, is not necessary for cell-cell junctions' establishment or maintenance, and is not affected by cell-cell junctions' and actin cytoskeleton disruption. These results reveal that two independent pools of N-cadherin exist on melanoma cell surface: one pool is independent of lipid rafts and is engaged in cell-cell junctions, while a second pool is localized in membrane rafts and does not participate in cell-cell adhesions. Targeting to membrane rafts may represent a previously unrecognized mechanism regulating N-cadherin function in melanoma cells.

Gaussian process framework for pervasive estimation of swimming velocity with body-worn IMU

Presented is an accurate swimming velocity estimation method using an inertial measurement unit (IMU) by employing a simple biomechanical constraint of motion along with Gaussian process regression to deal with sensor inherent errors. Experimental validation shows a velocity RMS error of 9.0 cm/s and high linear correlation when compared with a commercial tethered reference system. The results confirm the practicality of the presented method to estimate swimming velocity using a single low-cost, body-worn IMU.

Biomarkers of oxidative stress and its association with the urinary reducing capacity in bus maintenance workers.

BACKGROUND: Exposure to particles (PM) induces adverse health effects (cancer, cardiovascular and pulmonary diseases). A key-role in these adverse effects seems to be played by oxidative stress, which is an excess of reactive oxygen species relative to the amount of reducing species (including antioxidants), the first line of defense against reactive oxygen species. The aim of this study was to document the oxidative stress caused by exposure to respirable particles in vivo, and to test whether exposed workers presented changes in their urinary levels for reducing species.METHODS: Bus depot workers (n = 32) exposed to particles and pollutants (respirable PM4, organic and elemental carbon, particulate metal content, polycyclic aromatic hydrocarbons, NOx, O3) were surveyed over two consecutive days. We collected urine samples before and after each shift, and quantified an oxidative stress biomarker (8-hydroxy-2'-deoxyguanosine), the reducing capacity and a biomarker of PAH exposure (1-hydroxypyrene). We used a linear mixed model to test for associations between the oxidative stress status of the workers and their particle exposure as well as with their urinary level of reducing species.RESULTS: Workers were exposed to low levels of respirable PM4 (range 25-71 μg/m3). However, urinary levels of 8-hydroxy-2'-deoxyguanosine increased significantly within each shift and between both days for non-smokers. The between-day increase was significantly correlated (p < 0.001) with the concentrations of organic carbon, NOx, and the particulate copper content. The within-shift increase in 8OHdG was highly correlated to an increase of the urinary reducing capacity (Spearman ρ = 0.59, p < 0.0001).CONCLUSIONS: These findings confirm that exposure to components associated to respirable particulate matter causes a systemic oxidative stress, as measured with the urinary 8OHdG. The strong association observed between urinary 8OHdG with the reducing capacity is suggestive of protective or other mechanisms, including circadian effects. Additional investigations should be performed to understand these observations.

Changes in reproductive roles are associated with changes in gene expression in fire ant queens.

Abstract In species with social hierarchies, the death of dominant individuals typically upheaves the social hierarchy and provides an opportunity for subordinate individuals to become reproductives. Such a phenomenon occurs in the monogyne form of the fire ant, Solenopsis invicta, where colonies typically contain a single wingless reproductive queen, thousands of workers and hundreds of winged nonreproductive virgin queens. Upon the death of the mother queen, many virgin queens shed their wings and initiate reproductive development instead of departing on a mating flight. Workers progressively execute almost all of them over the following weeks. To identify the molecular changes that occur in virgin queens as they perceive the loss of their mother queen and begin to compete for reproductive dominance, we collected virgin queens before the loss of their mother queen, 6 h after orphaning and 24 h after orphaning. Their RNA was extracted and hybridized against microarrays to examine the expression levels of approximately 10 000 genes. We identified 297 genes that were consistently differentially expressed after orphaning. These include genes that are putatively involved in the signalling and onset of reproductive development, as well as genes underlying major physiological changes in the young queens.

Social chromosome variants differentially affect queen determination and the survival of workers in the fire ant Solenopsis invicta.

Intraspecific variation in social organization is common, yet the underlying causes are rarely known. An exception is the fire ant Solenopsis invicta in which the existence of two distinct forms of social colony organization is under the control of the two variants of a pair of social chromosomes, SB and Sb. Colonies containing exclusively SB/SB workers accept only one single queen and she must be SB/SB. By contrast, when colonies contain more than 10% of SB/Sb workers, they accept several queens but only SB/Sb queens. The variants of the social chromosome are associated with several additional important phenotypic differences, including the size, fecundity and dispersal strategies of queens, aggressiveness of workers, and sperm count in males. However, little is known about whether social chromosome variants affect fitness in other life stages. Here, we perform experiments to determine whether differential selection occurs during development and in adult workers. We find evidence that the Sb variant of the social chromosome increases the likelihood of female brood to develop into queens and that adult SB/Sb workers, the workers that cull SB/SB queens, are overrepresented in comparison to SB/SB workers. This demonstrates that supergenes such as the social chromosome can have complex effects on phenotypes at various stages of development.

A cross-sectional survey of attitudes to HIV risk and rapid HIV testing among clients of sex workers in Switzerland.

OBJECTIVES: To assess attitudes to HIV risk and acceptability of rapid HIV testing among clients of street-based female sex workers (FSW) in Lausanne, Switzerland, where HIV prevalence in the general population is 0.4%. METHODS: The authors conducted a cross-sectional study in the red light district of Lausanne for five nights in September of 2008, 2009 and 2010. Clients of FSW were invited to complete a questionnaire in the street assessing demographic characteristics, attitudes to HIV risk and HIV testing history. All clients interviewed were then offered anonymous finger stick rapid HIV testing in a van parked on-site. RESULTS: The authors interviewed 112, 127 and 79 clients in 2008, 2009 and 2010, respectively. All were men, average age 32-37 years old; 40-60% were in a stable relationship. History of unprotected sex was higher with non-commercial partners (33-50%) than with FSW (6-11%); 29-46% of clients had never undergone an HIV test. Anonymous rapid HIV testing was accepted by 45-50% of clients. Out of 109 HIV tests conducted during the three study periods, none was reactive. CONCLUSIONS: On-site HIV counselling and testing is acceptable among clients of FSW in this urban setting. These individuals represent an unquantified population, a proportion of which has an incomplete understanding of HIV risk in the face of high-risk behaviour, with implications for potential onward transmission to non-commercial sexual partners.