Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure

Background Childhood trauma exposures (CTEs) are frequent, well-established risk factor for the development of psychopathology. However, knowledge of the effects of CTEs in healthy individuals in a real life context, which is crucial for early detection and prevention of mental disorders, is incomplete. Here, we use ecological momentary assessment (EMA) to investigate CTE load-dependent changes in daily-life affective well-being and psychosocial risk profile in n = 351 healthy, clinically asymptomatic, adults from the community with mild to moderate CTE. Findings EMA revealed significant CTE dose-dependent decreases in real-life affective valence (p = 0.007), energetic arousal (p = 0.032) and calmness (p = 0.044). Psychosocial questionnaires revealed a broad CTE-related psychosocial risk profile with dose-dependent increases in mental health risk-associated features (e.g., trait anxiety, maladaptive coping, loneliness, daily hassles; p values < 0.003) and a corresponding decrease in factors protective for mental health (e.g., life satisfaction, adaptive coping, optimism, social support; p values < 0.021). These results were not influenced by age, sex, socioeconomic status or education. Conclusions Healthy community-based adults with mild to moderate CTE exhibit dose-dependent changes in well-being manifesting in decreases in affective valence, calmness and energy in real life settings, as well as a range of established psychosocial risk features associated with mental health risk. This indicates an approach to early detection, early intervention, and prevention of CTE-associated psychiatric disorders in this at-risk population, using ecological momentary interventions (EMI) in real life, which enhance established protective factors for mental health, such as green space exposure, or social support

BioOK – a Comprehensive System for Analysis and Risk Assessment of Genetically Modified Plants

Gentechnisch veränderte (GV) Pflanzen müssen im Rahmen des Zulassungsverfahrens in der EU auf ihre potentiellen Auswirkungen auf die Umwelt und die mensch­liche oder tierische Gesundheit analysiert werden. Der gegenwärtige Zulassungsprozess ist ein Konglo­merat verschiedenster Analysemethoden und extrem zeit- und kostenaufwendig. Das Anliegen von BioOK als ein multidisziplinäres wissenschaftliches Netzwerk ist die Entwicklung von maßgeschneiderten Ansätzen zur Risikoanalyse von GV Pflanzen auf der Grundlage von Ursache-Wirkungs­hypothesen mit dem Ziel des Aufbaus eines effektiven und qualifizierten Risikobewertungssystems. Die Forschungsaktivitäten von BioOK zielen auf einen Paradigmenwechsel im aktuellen Zulassungsprozess. Sie basieren auf einem modularen System, das alle Aspekte des Risikomanagements umfasst: molekulare Charakterisierung, Inhaltsstoffanalyse, agronomische Eigenschaften, Ziel- und Nichtzielorganismen, Boden und Mikroorganismen, Toxikologie, Allergenität und Überwachung nach Markt­einführung, wobei jeder Modul unterschiedliche Analysemethoden beinhaltet. Die durch BioOK angestrebte Reform des Risikobewertungsprozesses von GV Pflanzen umfasst zwei Phasen: zunächst die Optimierung der Analysemethoden selbst und dann die Etablierung eines Entscheidungsunterstützungssystems (Test Decision System – DSS), basierend auf biologischen Schwankungsbreiten (baselines), Zeigermerkmalen (indicators) und Grenzwerten (thresholds) für jede Analysemethode. BioOK hat in einer ersten Entwicklungsphase bereits optimierte Testmethoden entwickelt: Für die Inhaltsstoffanalyse wurde die Untersuchung auf substantielle Äquivalenz durch GC-MS, LC-MS und HPLC/RI Methoden vereinfacht. Ein neu eingeführtes Analyseschema zur Ermittlung potentieller Effekte von GV Pflanzen auf den Boden kombiniert ein in vitro System zur Beprobung von Rhizodepositaten von Pflanzen, die unter kontrollierten Umweltbedingen gewachsen sind, sowie die entsprechenden Bodentypen und deren Charakterisierung mit offenen und hochsensitiven molekular-chemischen Screening und Fingerprinting-Methoden. Ein neues in vitro System zur Simulation des Transports von Substanzen aus dem Darm ins Blut, das das Risiko der Aufnahme durch Mensch oder Tier zu einem frühen Zeitpunkt misst, wurde entwickelt. Um die Effektivität und Reproduzierbarkeit von Probenahmen an der Pflanze zu erhöhen, wird ein genau definiertes Probenahmeschema entwickelt. Schließlich, in Ergänzung der aktuellen Methodik zur Allgemeinen Überwachung (General Surveillance) von GV Pflanzen im Anbau, wurde eine Herangehensweise zur Abschätzung der Notwendigkeit für ein europaweites fallspezifisches (Case Specific) Monitoring beruhend auf Ursache-Wirkungsszenarien, erarbeitet. Die zweite Phase der BioOK F&amp;E-Arbeiten konzentriert sich auf die Entwicklung eines Entscheidungsunterstützungssystems (Decision Support System, DSS). Dazu wird ein computergestütztes System implementiert, in dem alle standardisierten und validierten Methoden zu einem Entscheidungsbaum mit Knotenpunkten, definiert über biologische Schwankungsbreiten und potentielle Risiken definierenden Grenzwerten für Zeigermerkmale, zusammengeführt sind. &nbsp; &nbsp;Genetically modified (GM) plants have to be analyzed for their potential impacts on the environment and on human or animal health before authorisation by the EU. The approval process currently refers to a conglomeration of diverse analytical methods and is intensive in time and costs. The intention of BioOK as a multidisciplinary scientific network is the development of tailor-made approaches for GM plants based on a cause-effect hypothesis to obtain an effective and qualified risk assessment system. The research activity of BioOK aims to renew the current approval process. It is based on a modular system covering all aspects of risk assessment: molecular characterisation, compound analysis, agronomic traits, target and non-target organisms, soil and micro organisms, toxicology, allergenicity and post-market monitoring, each module containing several test methods. The renewal of the risk assessment procedure intended by BioOK consists of two phases: first the optimization of test methods and second the establishment of a decision support system (DSS) based on baselines, indicators and thresholds developed for each of the methods. Optimized test methods have been developed mainly during the first phase: For compound analysis methods have been developed to ease the analysis of substantial equivalence of the events by GC-MS, LC-MS and HPLC/RI. A newly introduced testing scheme for the detection of potential effects of GM plants on soil combines an in-vitro system to collect rhizodeposits from plants grown under controlled environmental conditions and the correspon­ding bulk soil, and their characterisation by untargeted and highly sensitive molecular-chemical screening and fingerprinting technique. A novel in vitro system simula­ting the transport of substances from the gut into the blood that detects the risk of incorporation in human or animal at an early time point was developed. In order to increase the effectiveness and reproducibility of the sampling procedure we developed a valid defined sampling scheme. Finally, complementing the actual General Surveillance methodology, an approach for a Europe-wide case specific monitoring referring to cause-effect sce­narios was developed. The second phase concentrates on the development of a Decision Support System (DSS). A computer-based system will implement and merge all standardized methods in a decision tree system following decision rules defined by baseline and thresholds for indicators. &nbsp; &nbsp

Analysis of the IGF-system in milk from farm animals – Occurrence, regulation, and biomarker potential

IGFs and IGF-binding proteins (IGFBPs) are abundantly present in milk and in dairy products. Compared to the IGFs, the IGFBP have received less attention in milk, although truncated IGFBPs and IGFBP-glycosylation have been described in milk. Thereby, complex control of local IGF-effects can be assumed on the levels of IGFBPs, proteases, and protease inhibitors. The present review collects the current knowledge both on presence and regulation of IGFs and IGFBPs in milk particularly from dairy animal species. As a rule higher levels of IGF-I, IGF-II, and IGFBPs are measured around parturition if compared to later time-points of lactation. In all farm animal species included in this review, it is found that the relative abundancies of IGFBPs in milk and serum are similar, with IGFBP-3 and -2 characterized by higher concentrations if compared to IGFBP-4 or -5. The concentrations of IGFs and IGFBPs in milk or dairy products can be altered by hormones, dairy processing, or fermentation. Because milk can be used for non-invasive biomarker research, quality management, and health monitoring, we discuss novel directions of IGF-analysis and potential on-site biomarker research in milk

Circulating insulin-like growth factor-related biomarkers: Correlates and responses to calcium supplementation in colorectal adenoma patients

Circulating insulin-like growth factor 1 (IGF-1) may be directly associated with colorectal cancer risk, and IGF binding protein 3 (IGFBP-3) is one of the most abundantly expressed binding proteins in various cancers. Calcium intakes, primarily from food, have been directly associated with circulating IGF-1, but whether supplemental calcium affects IGF-1 and IGFBP-3 is unknown. We tested the effects of 1.0 and 2.0 grams of supplemental elemental calcium daily on circulating IGF-1 and IGFBP-3 concentrations in colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n=193). IGF-1 and IGFBP-3 were quantified using enzyme-linked immunoassay and quantitative Western Ligand blot, respectively. We also assessed cross-sectional associations of these biomarkers with participants’ baseline characteristics. We found no appreciable effect of calcium relative to placebo on circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio. Mean IGF-1 concentrations were 11.1% higher in those with greater milk intakes (P=0.05). Mean IGF-1 and IGFBP-3 concentrations were, respectively, 18.0% (P=0.003) and 16.5% (P=0.01) higher in men and were monotonically lower with increasing age (both P=0.01). IGFBP-3 was 17.7% higher among those with higher relative to no alcohol consumption (P=0.04). While these results support previous findings that IGF-1 concentrations are higher with greater milk intakes, and IGF-1 and IGFBP-3 concentrations differ according to sex and age, they provide no evidence to suggest that supplemental calcium appreciably affects circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio in sporadic colorectal adenoma patients

Increased Concentrations of Insulin-Like Growth Factor Binding Protein (IGFBP)-2, IGFBP-3, and IGFBP-4 Are Associated With Fetal Mortality in Pregnant Cows

Insulin-like growth factors (IGFs) play a critical role in fetal growth, and components of the IGF system have been associated with fetal growth restriction in women. In human pregnancy, the proteolytic cleavage of insulin-like growth factor binding proteins (IGFBPs), particularly IGFBP-4, releases free IGF for respective action at the tissue level. The aim of the present study was to determine IGFBP-2, IGFBP-3, and IGFBP-4 concentrations by Western ligand blotting during pregnancy until day 100 in cows and to compare these concentrations with those of non-pregnant cows and cows undergoing embryonic/fetal mortality. Therefore, two study trials (I and II) and an in vitro study were conducted. In study I, 43 cows were not pregnant, 34 cows were pregnant, and 4 cows were undergoing fm. In study II, 500 cows were examined, and 7 cases of pregnancy loss between days 24–27 and 34–37 after artificial insemination (AI, late embryonic mortality; em) and 8 cases of pregnancy loss between days 34–37 and 54–57 after AI (late embryonic mortality and early fetal mortality; em/fm) were defined from the analyses of 30 pregnant and 20 non-pregnant cows randomly selected for insulin-like growth factor 1 and IGFBP analyses. In vitro serum from pregnant (n = 3) and non-pregnant (n = 3) cows spiked after incubation with recombinant human (rh) IGFBP-4 for 24 h, and IGFBP-4 levels were analyzed before and after incubation to detect proteolytic degradation. The IGFBP-2, -3, and -4 concentrations did not decline during early pregnancy in cows, while IGFBP-4 concentrations were comparable between pregnant and non-pregnant cows, irrespective of low proteolytic activity, which was also demonstrated in cows. Interestingly, cows with em or fm showed distinct IGFBP patterns. The IGFBP-2 and -3 concentrations were higher (P &lt; 0.05) in cows with fm compared to pregnant. The IGFBP-4 levels were significantly higher in cows developing fm. Thus, distinct differences in the circulating IGFBP concentrations could be associated with late embryonic and early fetal losses in cattle

Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure

Abstract Background Childhood trauma exposures (CTEs) are frequent, well-established risk factor for the development of psychopathology. However, knowledge of the effects of CTEs in healthy individuals in a real life context, which is crucial for early detection and prevention of mental disorders, is incomplete. Here, we use ecological momentary assessment (EMA) to investigate CTE load-dependent changes in daily-life affective well-being and psychosocial risk profile in n = 351 healthy, clinically asymptomatic, adults from the community with mild to moderate CTE. Findings EMA revealed significant CTE dose-dependent decreases in real-life affective valence (p = 0.007), energetic arousal (p = 0.032) and calmness (p = 0.044). Psychosocial questionnaires revealed a broad CTE-related psychosocial risk profile with dose-dependent increases in mental health risk-associated features (e.g., trait anxiety, maladaptive coping, loneliness, daily hassles; p values < 0.003) and a corresponding decrease in factors protective for mental health (e.g., life satisfaction, adaptive coping, optimism, social support; p values < 0.021). These results were not influenced by age, sex, socioeconomic status or education. Conclusions Healthy community-based adults with mild to moderate CTE exhibit dose-dependent changes in well-being manifesting in decreases in affective valence, calmness and energy in real life settings, as well as a range of established psychosocial risk features associated with mental health risk. This indicates an approach to early detection, early intervention, and prevention of CTE-associated psychiatric disorders in this at-risk population, using ecological momentary interventions (EMI) in real life, which enhance established protective factors for mental health, such as green space exposure, or social support

Development of a Sensitive Bioassay for the Analysis of IGF-Related Activation of AKT/mTOR Signaling in Biological Matrices

The bioactivity of the IGF system is not a function of isolated hormone concentrations in a given biological matrix. Instead, the biological activities of IGFs are regulated by IGFBPs, IGFBP proteases, and inhibitors of IGFBP proteases. Therefore, assays based on IGF-related bioactivity may describe functions of the complete IGF system in a given biological matrix. Of particular interest are the IGF system effects on the AKT/mTOR pathway, as a dominant system for controlling growth, metabolism, and aging. In order to improve the sensitivity of IGF-dependent bioactivity, we made use of the known short-term and enhancing effects of IGFBP2 on the intracellular PI3K pathway. As a specific readout of this pathway, and further as a marker of the mTOR pathway, we assessed the phosphorylation of AKT-Ser473. Preincubation using IGFBP2 enhanced IGF1-dependent AKT-Ser473 phosphorylation in our experimental system. The assay’s specificity was demonstrated by inhibition of IGF1 receptors outside or inside the cell, using antiserum or small molecule inhibitors, which reduced AKT phosphorylation in response to exogenous IGF1 (p &lt; 0.05). The maximal response of AKT phosphorylation was recorded 15 to 60 min after the addition of IGF1 to cell monolayers (p &lt; 0.001). In our cellular system, insulin induced AKT phosphorylation only at supra-physiological concentrations (µM). Using this novel assay, we identified the differential biological activity of the IGF system in AKT-Ser473 phosphorylation in serum (mouse, naked mole rat, and human), in cerebrospinal fluid (human), and in colostrum or mature milk samples (dairy cow). We have developed a sensitive and robust bioassay to assess the IGF-related activation of the AKT/mTOR pathway. The assay works efficiently and does not require expensive cell culture systems. By using capillary immuno-electrophoresis, the readout of IGF-related bioactivity is substantially accelerated, requiring a minimum of hands-on time. Importantly, the assay system is useful for studying IGF-related activity in the AKT/mTOR pathway in a broad range of biological matrices

Additional file 1 of Dose-dependent changes in real-life affective well-being in healthy community-based individuals with mild to moderate childhood trauma exposure

Supplementary Material