Comparison of Calculated with Measured Oxygen Consumption in Children Undergoing Cardiac Catheterization

Our objective was to compare calculated (LaFarge) with measured oxygen consumption (VO2) using the AS/3 TM Compact Airway Module M-CAiOVX (Datex-Ohmeda, Helsinki, Finland; AS/3 TM) in children without cardiac shunts in a prospective, observational study. VO2 was determined at the end of the routine diagnostic and/or interventional catheterization. VO2was calculated according to the formula of LaFarge and Miettinen for each child and compared with the measured VO2. Data were compared using simple regression and Bland Altman analysis. Fifty-two children aged from 0.5 to 16years (median, 6.9years) and weighing 3.4 to 59.4kg (median, 22.9kg) were investigated. Calculated VO2values ranged from 59.0 to 230.8ml/min, and measured VO2 values from 62.7 to 282.2ml/min. Comparison of calculated versus measured VO2 values revealed a significant correlation (r=0.90, p<0.0001). Bias and precision were 8.9 and 48.3ml/min, respectively (95% limits of agreement: −39.4 to 57.2ml/min). Comparison of calculated VO2 in children older than 3 years (n=41), as restricted to the formula, with measured VO2, revealed a slightly reduced correlation (r=0.86, p<0.0001). Bias and precision were 10.0 and 52.5ml/min, respectively (95% limits of agreement: -42.4 to 62.5ml/min). We conclude that calculation of VO2 by the LaFarge formula does not provide reliable values compared to measured values. In clinical routine, measured rather than calculated VO2 values should be used for the estimation of cardiac output and related variable

From cell penetrating peptides to peptoids and polyamines as novel artificial molecular transporters

In recent years, RNA interference has gained a lot of importance as a tool for posttranscriptional silencing of genes due to its high specificity, efficiency and ease of application. In mammalian cells RNAi is triggered by the application of 21 bp short dsRNAs, so-called short interfering RNAs (siRNAs). Numerous studies indicate the great potential of RNAi in the therapy of viral infections and inherited diseases. Cell-penetrating peptides can be used to apply siRNAs to primary cells, non-dividing cells or fully grown organisms, that are diffcult to transfect. These short positively charged peptides are internalized by cells. They can be detected in the endosomes, lysosomes but also in the cytosol. If attached to CPPs, large cargo molecules can be taken up with a high efficiency that surpasses that of most conventional transfection methods. In the work presented here, peptide-coupled siRNAs (pepsiRNAs) have been developed as a novel tool for transient RNAi in mammalian cells. The peptides were attached to the siRNA by a disulfide bond, that is cleaved under the reducing conditions of the cytosol and thus releases the siRNA cargo. PepsiRNAs are readily taken up by many cell types that are difficult to address by conventional transfection methods. An siRNA-induced downregulation of the targeted genes was observed at concentrations between 10 and 100 nM. SiRNAs with a 5´-thiol modification upon their sense-strand were generated by in vitro transcription, for which a thiol-modified nucleotide was synthesized via an optimized route. The cell-penetrating peptides Penetratin and Tat were recombinantly expressed as fusion-proteins with glutathione-S-transferase (GST) and purified with a modified procedure to overcome the strong membrane interaction of the GST-tagged CPPs. Recombinant TEV protease was expressed to cleave the CPPs from the fusion tag, and the cleavage activity was assessed by comparison with commercially obtained TEV protease. Thus, alternative routes to the building blocks for pepsiRNAs have been provided to scale up the amount of pepsiRNAs. Finally, small molecules with cell-penetrating properties have been developed as a future replacement of the peptide moiety. Fluorescently labeled peptoids of differing length with amine-functionalized side chains have been shown to enter different mammalian cells lines at concentrations in the lower micromolar range by an endocytosis dependent mechanism. Cationic molecules as small as spermine attached to fluorescein are taken up by an endocytosis-related mechanism. By the same approach porphyrins were delivered into the interior of the cells, where they exhibited a cytotoxic effect upon illumination, so that spermine-coupled porphyrins may be developed into a novel drug for photodynamic therapy.Entwicklung neuer Delivery-Strategien für siRNAs - Von zellpenetrierenden Peptiden zu Peptoiden und Polyaminen als neuartige molekulare Transporter In den vergangenen Jahren, hat die RNA Interferenz (RNAi) aufgrund ihrer Spezifität, Effizienz und einfachen Anwendbarkeit eine große Bedeutung als Technik für das posttranskriptionale Gene-Silencing gewonnen. In Säugerzellen wird RNAi durch die Gabe von 21 bp kurzen doppelsträngigen RNAs, sogenannten short interfering RNAs (siRNAs), ausgelöst. Zahlreiche Studien belegen das große Potential dieser Methode für die Therapie viraler Infektionen und Erbkrankheiten. Um siRNAs auch in schlecht transfizierbare Systeme wie primäre und nicht-teilende Zellen bzw. ausgewachsene Organismen einzubringen, können zellpenetrierende Peptide (CPPs) verwendet werden. Diese kurzen positiv geladenen Peptide werden von Zellen aufgenommen, wo sie in Endosomen, Phagosomen, aber auch im Zytosol detektierbar sind. Verknüpft mit CPPs werden große Moleküle mit hoher Effizienz von Zellen aufgenommen, die die der meisten konventionellen Transfektionsmethoden übertrifft. In dieser Arbeit wurden peptidgekuppelte siRNAs (pepsiRNAs) als neue Methode zur transienten RNAi in Säugerzellen entwickelt. Hierzu wurden die Peptide über eine Disulfidbrücke mit den siRNAs verknüpft, unter den reduzierenden Bedingungen des Zytosols gespalten wird und , so dass die siRNA im Innern der Zelle freigesetzt wird. PepsiRNAs werden von einer Reihe von Zelltypen aufgenommen, die mit konventionellen Techniken nur schlecht behandelbar sind. Eine deutliche Herunterregulation der Ziel-Genprodukte wurde in einem Konzentrationsbereich von 10 -100 nM beobachtet. SiRNAs mit einer 5´-Thiolmodifikation am sense-Strang wurden durch in vitro Transkription gewonnen, für die ein thiolmodifizierten Nucleotid synthetisiert und dessen Synthese optimiert wurde. Die zellpenetrierenden Peptide Penetratin und Tat wurden rekombinant als Fusionproteine mit Gluatathion-S-Transferase (GST) exprimiert und mit modifizierten Verfahren gereinigt, um die starken Wechselwirkungen der GST-CPPs mit den Zellmembranen zu überwinden. Um die CPPs vom GST-Fusionstag zu trennen, wurde rekombinante TEV-Protease exprimiert und die Aktivität mit der von kommerziell erhältlicher TEV-Protease verglichen. Somit stehen nun Alternativen zur Festphasensynthese zur Verfügung, um die Bestandteile der pepsiRNAs in größeren Mengen herzustellen. Schließlich wurden kleine Moleküle mit zellpenetrierenden Eigenschaften als Ersatz für die Peptideinheit entwickelt. Es konnte gezeigt werden, dass fluoreszenzmarkierte Peptoide verschiedener Länge mit aminofunktionalisierten Seitenketten in Konzentrationen von einigen 10 µM von verschiedenen Säugerzelllinien durch einen endozytoseabhängigen Mechanismus aufgenommen werden. Selbst kleine positiv geladene Moleküle wie fluoresceinmarkiertes Spermin werden über einen endozytoseartigen Mechanismus aufgenommen. Auf diese Weise konnten auch Porphyrine ins Innere der Zellen gebracht werden, wo sie bei Belichtung ihre zytotoxische Wirkung entfalten, so dass sie als neuartiger Wirkstoff für die Photodynamische Therapie weiterentwickelt werden können

Lesiones no intencionadas infantiles en asentamientos precarios: campo de refugiados

Las lesiones no intencionadas son una causa de morbimortalidad emergente en niños y adultos jóvenes. El riesgo de lesiones aumenta en entornos precarios como lo son los campos de refugiados en los que, además, más de la mitad de la población desplazada en el mundo son niños. Los pocos datos publicados sobre lesiones no intencionadas en campos de refugiados sugieren una incidencia entre un 2,2 y un 39% de las consultas, siendo la causa más frecuente las caídas. El objetivo de este trabajo es determinar la incidencia de lesiones no intencionadas, sus condicionantes y las medidas preventivas en el asentamiento de Lóvua (Angola). Se realizó un análisis descriptivo retrospectivo de datos epidemiológicos de la actividad de 5 meses de las clínicas del campo y un análisis descriptivo cuantitativo y cualitativo de los factores de riesgo y medidas preventivas en el asentamiento. En Lóvua las lesiones no intencionadas representan el 1,02 % de las primeras consultas médicas, pero producen un elevado número de visitas en enfermería suponiendo un 88% de todas las curas. El 72% de las consultas de menores de 18 años por lesiones en enfermería son por traumáticas no intencionadas y el 28% por quemaduras. Los menores varones consultaron 1,56 veces más por lesiones traumáticas no intencionadas que las niñas (3,5 veces más en adultos). En el caso de las quemaduras las niñas consultaron 1,3 veces más que los niños (1,7 veces más en adultos). Se detectó un número relativamente alto de lesiones por animales incluyendo 2 fallecimientos por serpiente. En el asentamiento destacan factores de riesgo como la baja supervisión de los niños, cocinas a fuego abierto, fosas familiares no valladas, ausencia de zonas de juego seguras y presencia de animales venenosos. Factores protectores destacables son el adecuado espaciamiento y el empleo de energía solar. Para un análisis más preciso de las lesiones no intencionadas en el asentamiento de Lóvua haría falta una recogida de datos más detallada. Parece útil incluir el análisis de riesgos de lesiones no intencionadas en la planificación de campos de refugiados para poder aplicar medidas de prevención y mitigación adicionales a las recogidas en las guías según cada contexto específico.Unintentional injuries are an emerging cause of morbidity and mortality in children and young adults. The risk of injuries increases in precarious environments such as refugee camps. Moreover, more than half of the displaced population in the world are children. The few published data on unintentional injuries in refugee camps suggest an incidence between 2.2% and 39% of consultations and that falls are the leading cause. The goal of this work is to explore the incidence of unintentional injuries, their conditioners and preventive measures in the settlement of Lóvua (Angola). A retrospective descriptive analysis of epidemiological data from 5 months clinical activity and a quantitative and qualitative descriptive analysis of risk factors and preventive measures in the settlement were performed. In Lóvua unintentional injuries represent 1.02% of the first medical consultations, but they produce a high number of visits in nursing assuming 88% of all dressings. 72% of consultations of children (under 18 years of age) due to unintentional injuries in nursing are traumatic events and 28% are burns. Male minors consulted 1,56 times more for unintentional traumatic injuries than women (3,5 times in adults). In the case of burns feminine minors consulted 1,3 times more than males (1,7 times in adults). A relatively high number of animal-caused injuries was detected, including 2 deaths per snake. In the settlement of Lóvua the outstanding risk factors found were low supervision of children, open fire cooking, unfenced family pits, absence of safe play areas and the presence of poisonous animals. Outstanding protection factors were the adequate spacing and the use of solar energy. For a more accurate analysis of unintentional injuries in the settlement of Lóvua, further studies with detailed data collection would be necessary. It seems useful to include injury risk assessment in refugee camp planning, in order to apply additional prevention and mitigation measures to those already included in the humanitarian guides, according to each specific context.Máster Universitario en Acción Humanitaria Sanitaria (M161

Affective and cognitive theory of mind in posttraumatic stress, major depressive, and somatic symptom disorders: Association with childhood trauma

Objectives Childhood trauma constitutes a major risk factor for adult psychopathology, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and somatic symptom disorder (SSD). One potential mechanism linking childhood trauma to adult psychopathology may be alterations in theory of mind (ToM). Given the lack of transdiagnostic studies on the association between childhood trauma and ToM, further research is needed to elucidate whether and how childhood trauma relates to ToM impairments across and within diagnostic boundaries. Design A cross-sectional study design was applied. Methods A total of 137 individuals with varying levels of childhood trauma took part in this study, encompassing individuals with PTSD (n = 33), MDD (n = 33), SSD (n = 36), and healthy volunteers (HVs; n = 35). To assess ToM performance and childhood trauma, the Movie for the Assessment of Social Cognition was administered along with the Childhood Trauma Questionnaire. Results Only individuals with PTSD, but not individuals with MDD or SSD, showed a worse ToM performance compared to HVs. In the whole sample, childhood trauma correlated negatively with ToM performance. Exploratory group-specific analyses revealed higher levels of childhood trauma to be associated with more excessive ToM errors in individuals with SSD, and notably with an enhanced ToM performance in individuals with MDD. Conclusions Our results indicate associations between childhood trauma and ToM impairments in a large, transdiagnostic sample. Provided replication in future studies, our findings suggest ToM capacities as a promising treatment target for individuals exposed to severe childhood trauma, at least or particularly with a diagnosis of PTSD

Making sure that the emigration of healthcare personnel from Albania and BiH works for all: what Germany can do

The migration of healthcare professionals has detrimental impacts on socio-economic development in Albania and Bosnia-Herzegovina (BiH). Germany’s active recruitment of healthcare professionals contributes to this trend and thus adversely affects the goals of bilateral development cooperation. The Ministry of Economic Cooperation and Development should engage with the Ministries of Health and of Labour and Social Affairs to bolster the sustainability of the government’s inter-agency strategy on the recruitment of qualified workers (2019). A detailed whole-of-government approach needs to be put in place that further assesses and prevents adverse long-term demographic and socio-economic effects of emigration of care personnel in origin countries. The German Ministry of Health must ensure that legal and ethical standards for the recruitment of international personnel are observed. It should support the governments of Albania and BiH in monitoring the private mediation companies’ training and recruitment practices of nurses and medical technicians to avoid exploitative practices and adhesion contracts. The German Ministry for Economic Cooperation and Development should support programmes that provide equipment and know-how. Options for career advancement and training, safety measures and legal protection are the most urgent issues to prevent a care drain and need for medical tourism. The German Ministry for Economic Cooperation and Development should support such reforms through bilateral cooperation (technical advice) with Albania and BiH to counteract distortions of the labour market due to out-migration and to aid structural economic recovery. The attractiveness of alternative apprenticeships and job profiles needs to be increased, not least because the long-term attachment and increase of skilled workforce will positively affect the investment climate

Negative affect provides a context for increased distrust in the daily lives of individuals with a history of childhood maltreatment

Evidence on individuals affected by posttraumatic stress disorder (PTSD) following childhood maltreatment (CM) supports cognitive models suggesting that trauma engenders distrust and interpersonal threat sensitivity. We examined the associations between CM and both distrust and interpersonal threat sensitivity in daily life and investigated whether momentary negative affect (NA) provides a context that strengthens this association. Hypotheses were based on cognitive models of trauma and the feelings-as-information theory. In a 7-day ambulatory assessment study with six semirandom daily prompts (2,295 total), we measured self-reported momentary NA and assessed behavioral trust as well as interpersonal threat sensitivity via facial emotion ratings with two novel experimental paradigms in 61 participants with varying levels of CM (45,900 total trials). As hypothesized, NA was associated with increased momentary distrust, β = .03, p = .002, and interpersonal threat sensitivity, β = −.01, p = .021. Higher levels of CM were associated with more negative emotion ratings, independent of affective context, β = −.07, p = .003. Momentary behavioral distrust was associated with CM at high levels of momentary NA, β = .02, p = .027. The findings for both tasks support the feelings-as-information theory and suggest that cognitive alterations surrounding distrust and interpersonal threat, which were originally proposed for PTSD, likely also affect individuals with a history of CM

Coregulator Control of Androgen Receptor Action by a Novel Nuclear Receptor-Binding Motif

The androgen receptor (AR) is a ligand-activated transcription factor that is essential for prostate cancer development. It is activated by androgens through its ligand-binding domain (LBD), which consists predominantly of 11 α-helices. Upon ligand binding, the last helix is reorganized to an agonist conformation termed activator function-2 (AF-2) for coactivator binding. Several coactivators bind to the AF-2 pocket through conserved LXXLL or FXXLF sequences to enhance the activity of the receptor. Recently, a small compound-binding surface adjacent to AF-2 has been identified as an allosteric modulator of the AF-2 activity and is termed binding function-3 (BF-3). However, the role of BF-3 in vivo is currently unknown, and little is understood about what proteins can bind to it. Here we demonstrate that a duplicated GARRPR motif at the N terminus of the cochaperone Bag-1L functions through the BF-3 pocket. These findings are supported by the fact that a selective BF-3 inhibitor or mutations within the BF-3 pocket abolish the interaction between the GARRPR motif(s) and the BF-3. Conversely, amino acid exchanges in the two GARRPR motifs of Bag-1L can impair the interaction between Bag-1L and AR without altering the ability of Bag-1L to bind to chromatin. Furthermore, the mutant Bag-1L increases androgen-dependent activation of a subset of AR targets in a genome-wide transcriptome analysis, demonstrating a repressive function of the GARRPR/BF-3 interaction. We have therefore identified GARRPR as a novel BF-3 regulatory sequence important for fine-tuning the activity of the AR

Reduced vagal activity in borderline personality disorder is unaffected by intranasal oxytocin administration, but predicted by the interaction between childhood trauma and attachment insecurity

Individuals with borderline personality disorder (BPD) show self-regulatory deficits, associated with reduced heart-rate variability (HRV). However, results on reduced HRV in BPD remain heterogeneous, thus encouraging the search for developmental constructs explaining this heterogeneity. The present study first examined predictors of reduced resting-state HRV in BPD, namely the interaction between self-reported adult attachment insecurity and childhood trauma. Second, we investigated if alterations in resting-state HRV are modified by intranasal oxytocin administration, as oxytocin may enhance HRV and is implicated in the interaction between childhood trauma and disturbed attachment for the pathogenesis of BPD. In a randomized, placebo-controlled trial, 53 unmedicated women with BPD and 60 healthy controls (HC) self-administered either 24 I.U. of oxytocin or placebo and underwent a 4-min electrocardiogram. Our results replicate significantly reduced HRV in women with BPD, explained up to 16% by variations in childhood trauma and attachment insecurity. At high levels of acute attachment insecurity, higher levels of childhood trauma significantly predicted reduced HRV in BPD. However, our results do not support a significant effect of oxytocin on mean HRV, and no interaction effect emerged including childhood trauma and attachment insecurity. Our findings highlight a complex interaction between reduced vagal activity and developmental factors in BPD

A framework for the cross-sectoral integration of multi-model impact projections: land use decisions under climate impacts uncertainties

Climate change and its impacts already pose considerable challenges for societies that will further increase with global warming (IPCC, 2014a, b). Uncertainties of the climatic response to greenhouse gas emissions include the potential passing of large-scale tipping points (e.g. Lenton et al., 2008; Levermann et al., 2012; Schellnhuber, 2010) and changes in extreme meteorological events (Field et al., 2012) with complex impacts on societies (Hallegatte et al., 2013). Thus climate change mitigation is considered a necessary societal response for avoiding uncontrollable impacts (Conference of the Parties, 2010). On the other hand, large-scale climate change mitigation itself implies fundamental changes in, for example, the global energy system. The associated challenges come on top of others that derive from equally important ethical imperatives like the fulfilment of increasing food demand that may draw on the same resources. For example, ensuring food security for a growing population may require an expansion of cropland, thereby reducing natural carbon sinks or the area available for bio-energy production. So far, available studies addressing this problem have relied on individual impact models, ignoring uncertainty in crop model and biome model projections. Here, we propose a probabilistic decision framework that allows for an evaluation of agricultural management and mitigation options in a multi-impactmodel setting. Based on simulations generated within the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP), we outline how cross-sectorally consistent multi-model impact simulations could be used to generate the information required for robust decision making. Using an illustrative future land use pattern, we discuss the trade-off between potential gains in crop production and associated losses in natural carbon sinks in the new multiple crop- and biome-model setting. In addition, crop and water model simulations are combined to explore irrigation increases as one possible measure of agricultural intensification that could limit the expansion of cropland required in response to climate change and growing food demand. This example shows that current impact model uncertainties pose an important challenge to long-term mitigation planning and must not be ignored in long-term strategic decision making