Intraperitoneal Echinococcus multilocularis infection in mice modulates peritoneal CD4+ and CD8+ regulatory T cell development

Intraperitoneal proliferation of the metacestode stage of Echinococcus multilocularis in experimentally infected mice is followed by an impaired host immune response favoring parasite survival. We here demonstrate that infection in chronically infected mice was associated with a 3-fold increase of the percentages of CD4+ and CD8+ peritoneal T (pT) cells compared to uninfected controls. pT cells of infected mice expressed high levels of IL-4 mRNA, while only low amounts of IFN-gamma mRNA were detected, suggesting that a Th2-biased immune response predominated the late stage of disease. Peritoneal dendritic cells from infected mice (AE-pDCs) expressed high levels of TGF-beta mRNA and very low levels of IL-10 and IL-12 (p40) mRNA, and the expression of surface markers for DC-maturation such as MHC class II (Ia) molecules, CD80, CD86 and CD40 was down-regulated. In contrast to pDCs from non-infected mice, AE-pDCs did not enhance Concanavalin A (ConA)-induced proliferation when added to CD4+ pT and CD8+ pT cells of infected and non-infected mice, respectively. In addition, in the presence of a constant number of pDCs from non-infected mice, the proliferation of CD4+ pT cells obtained from infected animals to stimulation with ConA was lower when compared to the responses of CD4+ pT cells obtained from non-infected mice. This indicated that regulatory T cells (Treg) may interfere in the complex immunological host response to infection. Indeed, a subpopulation of regulatory CD4+ CD25+ pT cells isolated from E. multilocularis-infected mice reduced ConA-driven proliferation of CD4+ pT cells. The high expression levels of Foxp3 mRNA by CD4+ and CD8+ pT cells suggested that subpopulations of regulatory CD4+ Foxp3+ and CD8+ Foxp3+ T cells were involved in modulating the immune responses within the peritoneal cavity of E. multilocularis-infected mice.

A global ”imaging” view on systems approaches in immunology

The immune system exhibits an enormous complexity. High throughput methods such as the "-omic'' technologies generate vast amounts of data that facilitate dissection of immunological processes at ever finer resolution. Using high-resolution data-driven systems analysis, causal relationships between complex molecular processes and particular immunological phenotypes can be constructed. However, processes in tissues, organs, and the organism itself (so-called higher level processes) also control and regulate the molecular (lower level) processes. Reverse systems engineering approaches, which focus on the examination of the structure, dynamics and control of the immune system, can help to understand the construction principles of the immune system. Such integrative mechanistic models can properly describe, explain, and predict the behavior of the immune system in health and disease by combining both higher and lower level processes. Moving from molecular and cellular levels to a multiscale systems understanding requires the development of methodologies that integrate data from different biological levels into multiscale mechanistic models. In particular, 3D imaging techniques and 4D modeling of the spatiotemporal dynamics of immune processes within lymphoid tissues are central for such integrative approaches. Both dynamic and global organ imaging technologies will be instrumental in facilitating comprehensive multiscale systems immunology analyses as discussed in this review.

Global Change and the World's Mountains-Research Needs and Emerging Themes for Sustainable Development A Synthesis From the 2010 Perth II Conference

The conference on Global Change and the World’s Mountains held in Perth, Scotland, in 2010 offered a unique opportunity to analyze the state and progress of mountain research and its contribution to sustainable mountain development, as well as to reflect on required reorientations of research agendas. In this paper we provide the results of a three-step assessment of the research presented by 450 researchers from around the world. First, we determined the state of the art of mountain research and categorized it based on the analytical structure of the Global Land Project (GLP 2005). Second, we identified emerging themes for future research. Finally, we assessed the contribution of mountain research to sustainable development along the lines of the Grand Challenges in Global Sustainability Research (International Council for Science 2010). Analysis revealed that despite the growing recognition of the importance of more integrative research (inter- and transdisciplinary), the research community gathered in Perth still focuses on environmental drivers of change and on interactions within ecological systems. Only a small percentage of current research seeks to enhance understanding of social systems and of interactions between social and ecological systems. From the ecological systems perspective, a greater effort is needed to disentangle and assess different drivers of change and to investigate impacts on the rendering of ecosystem services. From the social systems perspective, significant shortcomings remain in understanding the characteristics, trends, and impacts of human movements to, within, and out of mountain areas as a form of global change. Likewise, sociocultural drivers affecting collective behavior as well as incentive systems devised by policy and decision makers are little understood and require more in-depth investigation. Both the complexity of coupled social– ecological systems and incomplete data sets hinder integrated systems research. Increased understanding of linkages and feedbacks between social and ecological systems will help to identify nonlinearities and thresholds (tipping points) in both system types. This presupposes effective collaboration between ecological and social sciences. Reflections on the Grand Challenges in Sustainability Research put forth by the International Council for Science (2010) reveal the need to intensify research on effective responses and innovations. This will help to achieve sustainable development in mountain regions while maintaining the core competence of mountain research in forecasting and observation.

The development and evaluation of a computer-based program to test and to teach the recognition of facial affect

Autism is a chronic pervasive neurodevelopmental disorder characterized by the early onset of social and communicative impairments as well as restricted, ritualized, stereotypic behavior. The endophenotype of autism includes neuropsychological deficits, for instance a lack of "Theory of Mind" and problems recognizing facial affect. In this study, we report the development and evaluation of a computer-based program to teach and test the ability to identify basic facially expressed emotions. 10 adolescent or adult subjects with high-functioning autism or Asperger-syndrome were included in the investigation. A priori the facial affect recognition test had shown good psychometric properties in a normative sample (internal consistency: rtt=.91-.95; retest reliability: rtt=.89-.92). In a prepost design, one half of the sample was randomly assigned to receive computer treatment while the other half of the sample served as control group. The training was conducted for five weeks, consisting of two hours training a week. The trained individuals improved significantly on the affect recognition task, but not on any other measure. Results support the usefulness of the program to teach the detection of facial affect. However, the improvement found is limited to a circumscribed area of social-communicative function and generalization is not ensured.

Development and simultaneous application of multiple care protocols in critical care: a multicenter feasibility study

OBJECTIVE: To test the feasibility of and interactions among three software-driven critical care protocols. DESIGN: Prospective cohort study. SETTING: Intensive care units in six European and American university hospitals. PATIENTS: 174 cardiac surgery and 41 septic patients. INTERVENTIONS: Application of software-driven protocols for cardiovascular management, sedation, and weaning during the first 7 days of intensive care. MEASUREMENTS AND RESULTS: All protocols were used simultaneously in 85% of the cardiac surgery and 44% of the septic patients, and any one of the protocols was used for 73 and 44% of study duration, respectively. Protocol use was discontinued in 12% of patients by the treating clinician and in 6% for technical/administrative reasons. The number of protocol steps per unit of time was similar in the two diagnostic groups (n.s. for all protocols). Initial hemodynamic stability (a protocol target) was achieved in 26+/-18 min (mean+/-SD) in cardiac surgery and in 24+/-18 min in septic patients. Sedation targets were reached in 2.4+/-0.2h in cardiac surgery and in 3.6 +/-0.2h in septic patients. Weaning protocol was started in 164 (94%; 154 extubated) cardiac surgery and in 25 (60%; 9 extubated) septic patients. The median (interquartile range) time from starting weaning to extubation (a protocol target) was 89 min (range 44-154 min) for the cardiac surgery patients and 96 min (range 56-205 min) for the septic patients. CONCLUSIONS: Multiple software-driven treatment protocols can be simultaneously applied with high acceptance and rapid achievement of primary treatment goals. Time to reach these primary goals may provide a performance indicator.

Impact of intraoperative behavior on surgical site infections

BACKGROUND: The aim of this study was to identify intraoperative risk factors for surgical site infections (SSIs), which are accessible to interventions. We evaluated the effect of extensive intraoperative antiseptic measures and the impact of the behavior of members of the surgical team on SSIs. METHODS: Standard versus extensive antiseptic measures were randomly assigned in 1,032 surgical patients. The adherence to principles of asepsis by members of the surgical team was assessed prospectively. RESULTS: The rate of SSI was 14% with standard antiseptic measures and 15% with extensive measures (P = .581). Multivariate analysis identified following independent risk factors: lapses in discipline (odds ratio [OR] 2.02, confidence interval [CI] 1.05-3.88), intestinal anastomosis (OR 6.74, CI 3.42-13.30), duration of operation more than 3 hours (OR 3.34, CI 1.82-6.14), and body mass index >30 kg/m2 (OR 1.98, CI 1.22-3.20). CONCLUSION: Extensive measures of antisepsis did not reduce the incidence of SSI. A lapse to adhere to principles of asepsis was identified as an independent risk factor for the development of SSI (ClinicalTrials.gov number, NCT00555815).

Development and pharmacokinetic characterization of pulmonal and intravenous delta-9-tetrahydrocannabinol (THC) in humans

The aim of the present study was to develop a physiologically compatible inhalation solution of delta-9-tetrahydrocannabinol (THC), and to compare the pharmacokinetic and analgesic properties of pulmonal THC versus pulmonal placebo and intravenous (iv) THC, respectively. Eight healthy volunteers were included in this randomized, double-blind, crossover study. The aqueous THC formulations were prepared by using a solubilization technique. iv THC (0.053 mg/kg body weight), pulmonal THC (0.053 mg/kg), or a placebo inhalation solution was administered as single dose. At defined time points, blood samples were collected, and somatic and psychotropic side effects as well as vital functions monitored. An ice water immersion test was performed to measure analgesia. Using a pressure-driven nebulizer, the pulmonal administration of the THC liquid aerosol resulted in high THC peak plasma levels within minutes. The bioavailability of the pulmonal THC was 28.7 +/- 8.2% (mean +/- SEM). The side effects observed after pulmonal THC were coughing and slight irritation of the upper respiratory tract, very mild psychotropic symptoms, and headache. The side effects after iv THC were much more prominent. Neither pulmonal nor iv THC significantly reduced experimentally induced pain.

Development of an array of ion-selective microelectrodes aimed for the monitoring of extracellular ionic activities

In this study, we present the development and the characterization of a generic platform for cell culture able to monitor extracellular ionic activities (K+, NH4+) for real-time monitoring of cell-based responses, such as necrosis, apoptosis, or differentiation. The platform for cell culture is equipped with an array of 16 silicon nitride micropipet-based ion-selective microelectrodes with a diameter of either 2 or 6 microm. This array is located at the bottom of a 200-microm-wide and 350-microm-deep microwell where the cells are cultured. The characterization of the ion-selective microelectrode arrays in different standard and physiological solutions is presented. Near-Nernstian slopes were obtained for potassium- (58.6 +/- 0.8 mV/pK, n = 15) and ammonium-selective microelectrodes (59.4 +/- 3.9 mV/pNH4, n = 13). The calibration curves were highly reproducible and showed an average drift of 4.4 +/- 2.3 mV/h (n = 10). Long-term behavior and response after immersion in physiological solutions are also presented. The lifetime of the sensors was found to be extremely long with a high recovery rate.

Development and validation of energy expenditure prediction models based on GT3X accelerometer data in 5- to 9-year-old children

Background: Accelerometry has been established as an objective method that can be used to assess physical activity behavior in large groups. The purpose of the current study was to provide a validated equation to translate accelerometer counts of the triaxial GT3X into energy expenditure in young children. Methods: Thirty-two children aged 5–9 years performed locomotor and play activities that are typical for their age group. Children wore a GT3X accelerometer and their energy expenditure was measured with indirect calorimetry. Twenty-one children were randomly selected to serve as development group. A cubic 2-regression model involving separate equations for locomotor and play activities was developed on the basis of model fit. It was then validated using data of the remaining children and compared with a linear 2-regression model and a linear 1-regression model. Results: All 3 regression models produced strong correlations between predicted and measured MET values. Agreement was acceptable for the cubic model and good for both linear regression approaches. Conclusions: The current linear 1-regression model provides valid estimates of energy expenditure for ActiGraph GT3X data for 5- to 9-year-old children and shows equal or better predictive validity than a cubic or a linear 2-regression model.

Development of Values after Compulsory School: Work comes first, then family

During school-to-work transition, adolescents develop values and prioritize what is im-portant in their life. Values are concepts or beliefs about desirable states or behaviors that guide the selection or evaluation of behavior and events, and are ordered by their relative importance (Schwartz & Bilsky, 1987). Stressing the important role of values, career re-search has intensively studied the effect of values on educational decisions and early career development (e.g. Eccles, 2005; Hirschi, 2010; Rimann, Udris, & Weiss, 2000). Few re-searchers, however, have investigated so far how values develop in the early career phase and how value trajectories are influenced by individual characteristics. Values can be oriented towards specific life domains, such as work or family. Work values include intrinsic and extrinsic aspects of work (e.g., self-development, cooperation with others, income) (George & Jones, 1997). Family values include the importance of partner-ship, the creation of an own family and having children (Mayer, Kuramschew, & Trommsdroff, 2009). Research indicates that work values change considerably during early career development (Johnson, 2001; Lindsay & Knox, 1984). Individual differences in work values and value trajectories are found e.g., in relation to gender (Duffy & Sedlacek, 2007), parental background (Loughlin & Barling, 2001), personality (Lowry et al., 2012), educa-tion (Battle, 2003), and the anticipated timing of school-to-work transition (Porfeli, 2007). In contrast to work values, research on family value trajectories is rare and knowledge about the development during the school-to-work transition and early career development is lack-ing. This paper aims at filling this research gap. Focusing on family values and intrinsic work values and we expect a) family and work val-ues to change between ages 16 and 25, and b) that initial levels of family and work values as well as value change to be predicted by gender, reading literacy, ambition, and expected du-ration of education. Method. Using data from 2620 young adults (59.5% females), who participated in the Swiss longitudinal study TREE, latent growth modeling was employed to estimate the initial level and growth rate per year for work and family values. Analyses are based on TREE-waves 1 (year 2001, first year after compulsory school) to 8 (year 2010). Variables in the models included family values and intrinsic work values, gender, reading literacy, ambition and ex-pected duration of education. Language region was included as control variable. Results. Family values did not change significantly over the first four years after leaving compulsory school (mean slope = -.03, p =.36). They increased, however, significantly five years after compulsory school (mean slope = .13, p >.001). Intercept (.23, p < .001), first slope (.02, p < .001), and second slope (.01, p < .001) showed significant variance. Initial levels were higher for men and those with higher ambitions. Increases were found to be steeper for males as well as for participants with lower educational duration expectations and reading skills. Intrinsic work values increased over the first four years (mean slope =.03, p <.05) and showed a tendency to decrease in the years five to ten (mean slope = -.01, p < .10). Intercept (.21, p < .001), first slope (.01, p < .001), and second slope (.01, p < .001) showed signifi-cant variance, meaning that there are individual differences in initial levels and growth rates. Initial levels were higher for females, and those with higher ambitions, expecting longer educational pathways, and having lower reading skills. Growth rates were lower for the first phase and steeper for the second phase for males compared to females. Discussion. In general, results showed different patterns of work and family value trajecto-ries, and different individual factors related to initial levels and development after compul-sory school. Developments seem to fit to major life and career roles: in the first years after compulsory school young adults may be engaged to become established in one's job; later on, raising a family becomes more important. That we found significant gender differences in work and family trajectories may reflect attempts to overcome traditional roles, as over-all, women increase in work values and men increase in family values, resulting in an over-all trend to converge.

Development of the Davos Assessment of Cognitive Biases Scale (DACOBS)

Objective: Cognitive problems and biases play an important role in the development and continuation of psychosis. A self-report measure of these deficits and processes was developed (Davos Assessment of Cognitive Biases Scale: DACOBS) and is evaluated in this study. Methods: An item pool made by international experts was used to develop a self-report scale on a sample of 138 schizophrenia spectrum patients. Another sample of 71 patients was recruited to validate the subscales. A group of 186 normal control subjects was recruited to establish norms and examine discriminative validity. Results: Factor analyses resulted in seven factors, each with six items (jumping to conclusions, belief inflexibility bias, attention for threat bias, external attribution bias, social cognition problems, subjective cognitive problems and safety behavior). All factors independently explained the variance (eigenvalues > 2) and total explained variance was 45%. Reliability was good (Cronbach's alpha = .90; split-half reliability = .92; test–retest reliability = .86). The DACOBS discriminates between schizophrenia spectrum patients and normal control subjects. Validity was affirmed for five of seven subscales. The scale ‘Subjective Cognitive problems’ was not associated with objective cognitive functioning and ‘Social cognition problems’ was not associated with the Hinting task, but with the scale measuring ideas of social reference. Conclusions: The DACOBS scale, with seven independent subscales, is reliable and valid for use in clinical practice and research.

Sympathy, distress, and prosocial behavior of preschool children in four cultures

This study examined emotional responding (sympathy and distress) and prosocial behavior as well as their relations across four cultures in a specific context. Preschool children (N = 212) from two Western cultures, Germany and Israel, and two South-East Asian cultures, Indonesia and Malaysia, participated in this study. Children's emotional reactions and prosocial behavior were observed when interacting with an adult in a quasi-experimental situation. Results showed that children from the two South-East Asian cultures, as compared to children from the two Western cultures, displayed more self-focused distress and less prosocial behavior. Across cultures, a positive relation between sympathy and prosocial behavior and a negative relation between self-focused distress and prosocial behavior were found. The strengths of these relations were moderated by culture. These results are discussed with regard to their cultural meaning in the specific experimental situation as well as to general culture-specific characteristics.

Adaptive Algorithms for Personalized Diabetes Treatment

Dynamic systems, especially in real-life applications, are often determined by inter-/intra-variability, uncertainties and time-varying components. Physiological systems are probably the most representative example in which population variability, vital signal measurement noise and uncertain dynamics render their explicit representation and optimization a rather difficult task. Systems characterized by such challenges often require the use of adaptive algorithmic solutions able to perform an iterative structural and/or parametrical update process towards optimized behavior. Adaptive optimization presents the advantages of (i) individualization through learning of basic system characteristics, (ii) ability to follow time-varying dynamics and (iii) low computational cost. In this chapter, the use of online adaptive algorithms is investigated in two basic research areas related to diabetes management: (i) real-time glucose regulation and (ii) real-time prediction of hypo-/hyperglycemia. The applicability of these methods is illustrated through the design and development of an adaptive glucose control algorithm based on reinforcement learning and optimal control and an adaptive, personalized early-warning system for the recognition and alarm generation against hypo- and hyperglycemic events.

CX3CR1+ cells facilitate the activation of CD4 T cells in the colonic lamina propria during antigen-driven colitis

Dendritic cells (DCs) and macrophages populate the intestinal lamina propria to initiate immune responses required for the maintenance of intestinal homeostasis. To investigate whether CX3CR1(+) phagocytes communicate with CD4 T cells during the development of transfer colitis, we established an antigen-driven colitis model induced by the adoptive transfer of DsRed OT-II cells in CX3CR1(GFP/+) × RAG(-/-) recipients challenged with Escherichia coli expressing ovalbumin (OVA) fused to a cyan fluorescent protein (CFP). After colonization of CX3CR1(GFP/+) × RAG(-/-) animals with red fluorescent E. coli pCherry-OVA, colonic CX3CR1(+) cells but not CD103(+) DCs phagocytosed E. coli pCherry-OVA. Degraded bacterial-derived antigens are transported by CD103(+) DCs to mesenteric lymph nodes (MLNs), where CD103(+) DCs prime naive T cells. In RAG(-/-) recipients reconstituted with OT II cells and gavaged with OVA-expressing E. coli, colonic CX3CR1(+) phagocytes are in close contact with CD4 T cells and presented bacterial-derived antigens to CD4 T cells to activate and expand effector T cells.

Simulating Cortical Development as a Self Constructing Process: A Novel Multi-Scale Approach Combining Molecular and Physical Aspects

Current models of embryological development focus on intracellular processes such as gene expression and protein networks, rather than on the complex relationship between subcellular processes and the collective cellular organization these processes support. We have explored this collective behavior in the context of neocortical development, by modeling the expansion of a small number of progenitor cells into a laminated cortex with layer and cell type specific projections. The developmental process is steered by a formal language analogous to genomic instructions, and takes place in a physically realistic three-dimensional environment. A common genome inserted into individual cells control their individual behaviors, and thereby gives rise to collective developmental sequences in a biologically plausible manner. The simulation begins with a single progenitor cell containing the artificial genome. This progenitor then gives rise through a lineage of offspring to distinct populations of neuronal precursors that migrate to form the cortical laminae. The precursors differentiate by extending dendrites and axons, which reproduce the experimentally determined branching patterns of a number of different neuronal cell types observed in the cat visual cortex. This result is the first comprehensive demonstration of the principles of self-construction whereby the cortical architecture develops. In addition, our model makes several testable predictions concerning cell migration and branching mechanisms.