Activation of the DNA damage response in vivo in synucleinopathy models of Parkinson\xe2\x80\x99s disease

The involvement of DNA damage and repair in aging processes is well established. Aging is an unequivocal risk factor for chronic neurodegenerative diseases, underscoring the relevance of investigations into the role that DNA alterations may have in the pathogenesis of these diseases. Consistently, even moderate impairment of DNA repair systems facilitates the onset of pathological features typical of PD that include derangement of the dopaminergic system, mitochondrial dysfunction, and alpha-synuclein stress. The latter establishes a connection between reduced DNA repair capacity and a cardinal feature of PD, alpha-synuclein pathology. It remains to be determined, however, whether alpha-synuclein stress activates in vivo the canonical signaling cascade associated with DNA damage, which is centered on the kinase ATM and substrates such as \xce\xb3H2Ax and 53BP1. Addressing these issues would shed light on age-related mechanisms impinging upon PD pathogenesis and neurodegeneration in particular. We analyzed two different synucleinopathy PD mouse models based either on intranigral delivery of AAV-expressing human alpha-synuclein, or intrastriatal injection of human alpha-synuclein pre-formed fibrils. In both cases, we detected a significant increase in \xce\xb3H2AX and 53BP1 foci, and in phospho-ATM immunoreactivity in dopaminergic neurons, which collectively indicate DNA damage and activation of the DNA damage response. Mechanistic experiments in cell cultures indicate that activation of the DNA damage response is caused, at least in part, by pro-oxidant species because it is prevented by exogenous or endogenous antioxidants, which also rescue mitochondrial anomalies caused by proteotoxic alpha-synuclein. These in vivo and in vitro findings reveal that the cellular stress mediated by alpha-synuclein\xe2\x80\x94a pathological hallmark in PD\xe2\x80\x94elicits DNA damage and activates the DNA damage response. The toxic cascade leading to DNA damage involves oxidant stress and mitochondrial dysfunction The data underscore the importance of DNA quality control for preservation of neuronal integrity and protection against neurodegenerative processes

The importance of job control for workers with decreased work ability to remain productive at work

Purpose: Workers with decreased work ability are at greater risk of reduced productivity at work. We hypothesized that work-related characteristics play an important role in supporting workers to remain productive despite decreased work ability. Methods: The study population consisted of 10,542 workers in 49 different companies in the Netherlands in 2005-2009. Productivity loss at work was defined on a 10-point scale by asking how much work was actually performed during regular hours on the last regular workday when compared with normal. Independent variables in the logistic regression analysis were individual characteristics, work-related factors, and the work ability index. Additive interactions between work-related factors and decreased work ability were evaluated by the relative excess risk due to interaction (RERI). Results: The odds ratios and 95% confidence intervals (CI) for the likelihood of productivity loss at work were 2.03 (1.85-2.22), 3.50 (3.10-3.95), and 5.54 (4.37-7.03) for a good, moderate, and poor work ability, compared with an excellent work ability (reference group). Productivity loss at work was associated with lack of job control, poor skill discretion, and high work demands. There was a significant interaction between decreased work ability and lack of job control (RERI = 0.63 95% CI 0.11-1.16) with productivity loss at work. Conclusion: The negative effects on work performance of decreased work ability may be partly counterbalanced by increased job control. This suggests that interventions among workers with (chronic) disease that cause a decreased work ability should include enlargement of possibilities to plan and pace their own activities at work

Beneficial effects of sitostanol on the attenuated immune function in asthma patients: results of an in vitro approach.

BACKGROUND: In vitro and animal studies have suggested that plant sterols and stanols increase cytokine production by T-helper-1 cells. This may be beneficial for patient groups characterized by a T-helper-2 dominant immune response, e.g. asthma patients. (1) to evaluate whether sitostanol induces a T-helper-1 shift in peripheral blood mononuclear cells (PBMCs) from asthma patients, and (2) to unravel the role of regulatory T-cells in this respect. METHODOLOGY/PRINCIPAL FINDINGS: PBMCs from 10 asthma patients and 10 healthy subjects were isolated and incubated with 1.2 µM sitostanol, while stimulated with 5 µg/ml PHA. Similar amounts of cholesterol were used to determine whether effects were specific for plant stanols or for sterols in general. Changes in cytokine production were measured using antibody arrays and ELISAs. Changes in regulatory T-cell population size were measured by flow cytometry, using intracellular Foxp3 staining. Sitostanol increased production of IFNγ by 6.5% and IL-2 by 6.0% compared to cholesterol (p<0.01). No changes in IL-4 and IL-13 were found. Interestingly, this effect was only present in PBMCs from asthma patients. The number of Foxp3+ cells tended to increase and their activity, measured by IL-10 production, increased after sitostanol treatment in PBMCs from asthma patients compared to controls by 32.3% (p = 0.077) and 13.3% (p<0.05), respectively. CONCLUSIONS/SIGNIFICANCE: Altogether, the sitostanol-induced Thelper-1 shift in PBMCs from asthma patients and the stimulating effects of sitostanol on Treg cell numbers and activity indicate a possible novel approach for plant stanol ester enriched functional foods in the amelioration of asthmatic symptoms. Functional effects, however, require further evaluation

Capable and credible? Challenging nutrition science

Nutrition science has enriched our understanding of how to stay healthy by producing valuable knowledge about the interaction of nutrients, food, and the human body. Nutrition science also has raised societal awareness about the links between food consumption and well-being, and provided the basis for food regulations and dietary guidelines. Its collaborative and interdisciplinary research has accomplished much, scientifically and socially. Despite this, nutrition science appears to be in crisis and is currently confronted with a public reluctance to trust nutritional insights. Though deflating trust is a general phenomenon surrounding the scientific community, its impact on nutrition science is particularly strong because of the crucial role of nutrition in everyone’s daily life. We, a Dutch collective of nutritionists, medical doctors, philosophers and sociologists of science (http://www.nutritionintransition.nl), have diagnosed that nutrition science is meeting inherent boundaries. This hampers conceptual and methodological progress and the translation of novel insights into societal benefit and trust. In other words, nutrition science is facing limitations to its capability and credibility, impeding its societal value. We take up the challenge to halt the threatening erosion of nutrition science’s capability and credibility, and explore a way forward. We analyse limitations to capability and credibility, then argue that nutrition science is caught in a vicious circle, and end by offering some suggestions to transcend the limitations and escape the current deadlock. We invite nutritional experts as well as scholars from adjacent disciplines to engage in the discussion

Baseline subject characteristics.

<p>Baseline subject characteristics.</p

Effects of sitostanol and cholesterol on NK cells, NKT cells and CD107a expression after exposure to K562 cells.

<p>Sitostanol significantly reduced the percentage of NK cells in asthma patients as well as in healthy controls (p<0.05). Cholesterol lowered the activity of NK cells in asthma patients (p<0.05) and sitostanol did not increase the activity of NKT cells in asthma patients, but only in healthy controls (p<0.05). a = p<0.05 v cyclodextrin; b = p<0.10 v cholesterol; c = p<0.05 v sitostanol; d = p<0.10 v asthma patients.</p

Cytokine responses upon stimulation with a purified House Dust Mite extract.

<p>PBMCs from asthma patients tended to produce more IL-13 than cells from healthy controls (1632 pg/mL v 695 pg/mL, p = 0.096). Other cytokines did not differ between asthma patients and healthy controls. Data are presented as single values and medians. # p<0.10.</p

Baseline cell counts and CD107a expression.

<p>Healthy controls and asthma patients did not differ at baseline, apart from the percentage of NK cells in the PBMC population where asthma patients had a significantly higher NK cell count (9.66% v 2.17%, p<0.05). Data are presented as mean ± SD or median (range).</p>*<p>p<0.05.</p

Based on the results of this pilot study we suggest the above pathway in which sitostanol induces IL-2 production in Th1 cells, which leads to the proliferation of Treg cells.

<p>These cells will produce higher amounts of IL-10, that can inhibit the activity of the dominant Th2 cells, which might ultimately lead to a relief of asthmatic symptoms.</p