Treg-Therapy Allows Mixed Chimerism and Transplantation Tolerance Without Cytoreductive Conditioning

Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-β induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach

Pregnant women with bronchial asthma benefit from progressive muscle relaxation: A randomized, prospective, controlled trial

Background: Asthma is a serious medical problem in pregnancy and is often associated with stress, anger and poor quality of life. The aim of this study was to determine the efficacy of progressive muscle relaxation (PMR) on change in blood pressure, lung parameters, heart rate, anger and health-related quality of life in pregnant women with bronchial asthma. Methods: We treated a sample of 64 pregnant women with bronchial asthma from the local population in an 8-week randomized, prospective, controlled trial. Thirty-two were selected for PMR, and 32 received a placebo intervention. The systolic blood pressure, forced expiratory volume in the first second, peak expiratory flow and heart rate were tested, and the State-Trait Anger Expression Inventory and Health Survey (SF-36) were employed. Results: According to the intend-to-treat principle, a significant reduction in systolic blood pressure and a significant increase in both forced expiratory volume in the first second and peak expiratory flow were observed after PMR. The heart rate showed a significant increase in the coefficient of variation, root mean square of successive differences and high frequency ranges, in addition to a significant reduction in low and middle frequency ranges. A significant reduction on three of five State-Trait Anger Expression Inventory scales, and a significant increase on seven of eight SF-36 scales were observed. Conclusions: PMR appears to be an effective method to improve blood pressure, lung parameters and heart rate, and to decrease anger levels, thus enhancing health-related quality of life in pregnant women with bronchial asthma. Copyright (c) 2006 S. Karger AG, Basel

Belief in a zero-sum game and subjective well-being across 35 countries

This article presents a short research report on the relationship between perceived antagonism in social relations measured using the Belief in a Zero-Sum Game (BZSG) scale, life satisfaction, and positive and negative affect. Given that individuals who believe that life is like a zero-sum game are likely to perceive their daily interactions with others as unfair, we expected that individuals with high BZSG experience more negative affect and fewer positive one, resulting in a lower satisfaction with life. In addition, we examined whether country-level BZSG may play a moderating role in these associations. Data were collected from student samples (N = 7146) in 35 countries. Multilevel modelling revealed that perceived social antagonism in social relations is negatively associated with satisfaction with life and that this relationship is mediated by both positive and negative affect at the individual level. The relation of individual BZSG and negative affect on satisfaction with life were weaker in societies with higher country-level BZSG, suggesting that the effects of BZSG may be less detrimental in these countries. These findings extend previous knowledge about predictors of life satisfaction and suggest that social beliefs might also be an important factor that influences subjective well-being. The contribution of the study is that the separate treatment of life satisfaction and positive and negative affect may be helpful in many research situations, particularly from a cross-cultural perspective.info:eu-repo/semantics/publishedVersio

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood–brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, logP, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Worker or Shirker - Who Evades More Taxes? A Real Effort Experiment

With the help of a real effort experiment, we analyze if tax evasion depends on the amount of effort invested to generate income. In three treatments, subjects were either endowed with income or had to work moderately or hard to earn it. In line with prospect theory, subjects evaded more taxes when they worked hard for their income. We find little evidence for the prediction that tax evasion in the endowed treatment is higher than in the moderate work treatment