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ZusammenfassungDigitales Lernen in religiösen Bildungsprozessen befasst sich besonders mit medienethischen Fragestellungen. Sexting und Cybermobbing werden als riskantes Mediennutzungsverhalten von Jugendlichen bewertet. Im Rahmen der schulischen Präventionsarbeit wird daher vor allem die Schuldfrage thematisiert. Die besondere Herausforderung für die Religionspädagogik besteht in der Wahrnehmung der Schamerfahrungen für die Identitätsentwicklung von Mädchen und Jungen in den erweiterten sozialen Räumen der digitalen Kommunikationsmittel. In Anlehnung an die Schamethik von Klaas Huizing und der medienweltorientierten Religionsdidaktik von Manfred Pirner verfolgt eine evangelische Mediennutzungsethik der Schamsensibilisierung (Kristian Fechtner) das Ziel der Kompetenzentwicklung von Mitgefühl und Widerstandsfähigkeit.
Growth corridors have been an instrument of
economic development for decades but have gained new
attention in regional economic development policies in recent years, e.g., in Sub-Saharan Africa or Southeast Asia.
They are seen by policy makers and private businesses as
catalysts of regional economic integration, pushing traditional businesses into increasingly complex international
value chains. However, the outcomes of such development
initiatives are still barely understood. Critics argue that development policies are based on simplified models that are
unable to sufficiently address the complexity of regional
development. Policies on value-chain development, for
example, can lead to conflicts, external dependencies,
land rush, and a polarization of wealth. Growth corridors
often go hand-in-hand with socio-economic transformations and land-use conflicts. This paper first discusses the
theoretically possible desired and undesired regional socio-economic effects of modern corridors. Second, we illustrate the potential and challenges to realize integrative
(or inclusive) development by contrasting three growth
corridors: the SAGCOT growth corridor in Tanzania, the
Walvis Bay-Ndola-Lubumbashi Development Corridor
(WBNLDC) in Namibia, Zambia and Zimbabwe, and the
growth corridors in the Greater Mekong Subregion (GMS)
Der Beitrag behandelt eine Problematik aus dem Bereich der
mittelbaren Täterschaft gem. § 25 I Alt. 2 StGB, die spätestens seit der berühmten Entscheidung des Bundesgerichtshofs im Mauerschützenfall (BGHSt 40, 218) zu den umstrittensten Fragen der deutschen Beteiligungsdogmatik zählt:
die Rechtsfigur der Organisationsherrschaft und ihre prinzipielle Übertragbarkeit auf Wirtschaftsunternehmen. Anliegen des Beitrags ist es, die Entwicklung der Organisationsherrschaft nachzuzeichnen, das kaum mehr überschaubaren
Meinungsspektrum zur Thematik in seinen wesentlichen
Leitlinien zusammenzufassen und so das nötige examensrelevante Wissen für das universitäre Schwerpunktstudium
zu vermitteln.
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
For the last two decades, heparins have been widely used as anticoagulants. Besides
numerous advantages, up to 5% patients with heparin administration suffer from a major adverse
drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep
vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and
a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using
single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding
mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in
typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT
caused by a subset of human-derived antibodies in patients without heparin exposure. The findings
proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review,
the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms
inducing thrombocytopenia by both heparins and antibodies will be discussed.
: An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased
mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be
a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT)
is currently in the interest of research due to its potential inhibitory effects on IDO1 and
immunomodulatory properties. The present study aims to investigate the protective and
immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine
in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan
(TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite
kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils
and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP
to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that
degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide
no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven
interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be
considered for therapeutic applications of 1-MT.
The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin
(1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens.
Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment
strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT),
where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive
oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is
5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment
of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT
and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different
tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity
were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the
combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also
observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels
were observed after combination but apoptosis induction was not necessarily increased compared
to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic
subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion,
pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards
Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.
Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells
(B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The
function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and
peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed
in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to
S1P was studied in vitro. The role of S1P signalling was further explored in a s1p4
−/− mouse
strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4
(S1P1 and S1P4, respectively). S1P1 showed differential expression between the distinct peritoneal B
cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration
response to S1P. s1p4
−/− mice displayed significant alterations in the composition of peritoneal
B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA) in the
gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P4 deficiency alters the
composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest
that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies.
Abstract
Identifying materials with an efficient spin-to-charge conversion is crucial for future spintronic applications. In this respect, the spin Hall effect is a central mechanism as it allows for the interconversion of spin and charge currents. Spintronic material research aims at maximizing its efficiency, quantified by the spin Hall angle and the spin-current relaxation length . We develop an all-optical contact-free method with large sample throughput that allows us to extract and . Employing terahertz spectroscopy and an analytical model, magnetic metallic heterostructures involving Pt, W and Cu80Ir20 are characterized in terms of their optical and spintronic properties. The validity of our analytical model is confirmed by the good agreement with literature DC values. For the samples considered here, we find indications that the interface plays a minor role for the spin-current transmission. Our findings establish terahertz emission spectroscopy as a reliable tool complementing the spintronics workbench.
III Reviews
(2018)
One of the major problems in the study of the dynamics of proteins is the visualization of changing conformations that are important for processes ranging from enzyme catalysis to signaling. A protein exhibiting conformational dynamics is the soluble blood protein beta 2-glycoprotein I (beta2GPI), which exists in two conformations: the closed (circular) form and the open (linear) form. It is hypothesized that an increased proportion of the open conformation leads to the autoimmune disease antiphospholipid syndrome (APS). A characteristic feature of beta2GPI is the high content of lysine residues. However, the potential role of lysine in the conformational dynamics of beta2GPI has been poorly investigated. Here, we report on a strategy to permanently open up the closed protein conformation by chemical acetylation of lysine residues using acetic acid N-hydroxysuccinimide ester (NHS-Ac). Specific and complete acetylation was demonstrated by the quantification of primary amino groups with fluoraldehyde o-phthalaldehyde (OPA) reagent, as well as western blot analysis with an anti-acetylated lysine antibody. Our results demonstrate that acetylated beta2GPI preserves its secondary and tertiary structures, as shown by circular dichroism spectroscopy. We found that after lysine acetylation, the majority of proteins are in the open conformation as revealed by atomic force microscopy high-resolution images. Using this strategy, we proved that the electrostatic interaction of lysine residues plays a major role in stabilizing the beta2GPI closed conformation, as confirmed by lysine charge distribution calculations. We foresee that our approach will be applied to other lysine-rich proteins (e.g. histones) undergoing conformational transitions. For instance, conformational dynamics can be triggered by environmental conditions (e.g. pH, ion concentration, post-translational modifications, and binding of ligands). Therefore, our study may be relevant for investigating the equilibrium of protein conformations causing diseases.
Zielstellung: In dieser prospektiven Arbeit überprüften wir, ob ein sequenzbasierter Softwarealgorithmus zur Geräuschreduktion in der Magnetresonanztomographie (MRT) einen Einfluss auf die Bildqualität und das Signal-zu-Rauschverhältnis (SNR) besitzt.
Material und Methoden: Einunddreißig Patienten, 18 Männer, 13 Frauen, Durchschnittsalter 58,3 ± 14,5 Jahren, unterzogen sich einer indizierten, kranialen MRT-Bildgebung. Das Sequenzprotokoll schloss FLAIR-Sequenzen ein, welche mit identischen Scanparametern jeweils mit und ohne Anwendung des Softwarealgorithmus Quiet Suite (QS) (Siemens Healthcare) angefertigt wurden. Mit Hilfe eines Schalldruckpegelmessgerätes (Testo, Typ 815) wurden die maximalen Lautstärkepegel für beide Sequenzen im Untersuchungsraum ermittelt. Es erfolgte die subjektive Beurteilung der Bildqualität auf einer Fünf-Punkte-Skala (1 sehr gut - 5 inadäquat) durch zwei Radiologen unabhängig voneinander. Separat wurde das SNR für die graue Hirnsubstanz, weiße Hirnsubstanz und den Liquor für beide Sequenzen ermittelt. Zusätzlich erfolgte die Auswertung von Detektionsraten pathologischer Läsionen innerhalb der weißen Hirnsubstanz jeweils mit und ohne Verwendung von QS. Die statistische Analyse mit dem Vergleich beider Sequenzen erfolgte mittels Mann-Whitney-U-Test.
Ergebnisse: Unsere Ergebnisse zeigen, dass die Verwendung von QS die Schalldruckpegelspitzen signifikant reduziert (83,5 ± 7,3 dB(A) versus 81,5 ± 7,5 dB(A) mit QS, p ≤ 0,017). Hinsichtlich der Beurteilung der subjektiven Bildqualität wurden keine signifikanten Unterschiede zwischen beiden Befundern ermittelt (Befunder 1: 2,03/2,07, p = 0,730; Befunder 2: 1,98/2,10, p = 0,362). QS führte für ausgewählte Bereiche zu einem Anstieg des SNR (graue Substanz, p ≤ 0,001; weiße Substanz p = 0,006). Die Detektionsraten von suspekten Läsionen innerhalb der weißen Substanz zeigten keine signifikanten Unterschiede unter Verwendung von QS (Befunder 1, p = 0,944; Befunder 2, p = 0,952).
Schlussfolgerungen: Sequenzbasierte Softwarealgorithmen, wie QS, besitzen das Potential die Schalldruckpegelspitzen in der MRT signifikant zu reduzieren ohne die subjektive Bildqualität zu kompromittieren oder die diagnostische Genauigkeit zu gefährden.
We aimed to evaluate the outcome of different treatment modalities for extremity venous thrombosis (VT) in neonates and infants, highlighting the current debate on their best tool of management. This retrospective study took place over a 9-year period from January 2009 to December 2017. All treated patients were referred to the vascular and pediatric surgery departments from the neonatal intensive care unit. All patients underwent a thorough history-taking as well as general clinical and local examination of the affected limb. Patients were divided into 2 groups: group I included those who underwent a conservative treated with the sole administration of unfractionated heparin (UFH), whereas group II included those who were treated with UFH plus warfarin. Sixty-three patients were included in this study. They were 36 males and 27 females. Their age ranged from 3 to 302 days. Forty-one (65%) patients had VT in the upper limb, whereas the remaining 22 (35%) had lower extremity VT. The success rate of the nonsurgical treatment was accomplished in 81% of patients. The remaining 19% underwent limb severing, due to established gangrene. The Kaplan-Meier survival method revealed a highly significant increase in both mean and median survival times in those groups treated with heparin and warfarin compared to heparin-only group (P < .001). Nonoperative treatment with anticoagulation or observation (ie, wait-and-see policy) alone may be an easily applicable, effective, and a safe modality for management of VT in neonates and infants, especially in developing countries with poor or highly challenged resource settings.
With improvements in breast imaging, mammography, ultrasound and minimally invasive interventions, the detection of early breast cancer, non-invasive cancers, lesions of uncertain malignant potential, and benign lesions has increased. However, with the improved diagnostic capabilities comes a substantial risk of false-positive benign lesions and vice versa false-negative malignant lesions. A statement is provided on the manifestation, imaging, and diagnostic verification of isolated benign breast tumours that have a frequent manifestation, in addition to general therapy management recommendations. Histological evaluation of benign breast tumours is the most reliable diagnostic method. According to the S3 guideline and information gained from analysis of the literature, preference is to be given to core biopsy for each type of tumour as the preferred diagnostic method. An indication for open biopsy is also to be established should the tumour increase in size in the follow-up interval, after recurring discrepancies in the vacuum biopsy results, or at the request of the patient. As an alternative, minimally invasive procedures such as therapeutic vacuum biopsy, cryoablation or high-intensity focused ultrasound are also becoming possible alternatives in definitive surgical management. The newer minimally invasive methods show an adequate degree of accuracy and hardly any restrictions in terms of post-interventional cosmetics so that current requirements of extensive breast imaging can be thoroughly met.
Significance of Hyperbaric Oxygenation in the Treatment of Fournier’s Gangrene: A Comparative Study
(2018)
Introduction: Hyperbaric oxygenation (HBO), in addition to anti-infective and surgical therapy, seems to be a key treatment point for Fournier’s gangrene. The aim of this study was to investigate the influence of HBO therapy on the outcome and prognosis of Fournier’s gangrene. Patients and Methods: In the present multicenter, retrospective observational study, we evaluated the data of approximately 62 patients diagnosed with Fournier’s gangrene between 2007 and 2017. For comparison, 2 groups were distinguished: patients without HBO therapy (group A, n = 45) and patients with HBO therapy (group B, n = 17). The analysis included sex, age, comorbidities, clinical symptoms, laboratory and microbiological data, debridement frequency, wound dressing, antibiotic use, outcome and prognosis. The statistical analysis was performed with GraphPad Prism 7® (GraphPad Software, Inc., La Jolla, USA). Results: Demographic data showed no significant differences. The laboratory parameters C-reactive protein and urea were significantly higher in group B (group B: 301.7 vs. 140.6 mg/dL; group A: 124.8 vs. 54.7 mg/dL). Sepsis criteria were fulfilled in 77.8 and 100% of the patients in groups A and B respectively. Treatment in the intensive care unit (ICU) was therefore indicated in 69% of the patients in group A and 100% of the patients in group B. The mean ICU stay was 9 and 32 days for patients in groups A and B respectively. The wound debridement frequency and hospitalization stay were significantly greater in group B (13 vs. 5 debridement and 40 vs. 22 days). Initial antibiosis was test validated in 80% of the patients in group A and 76.5% of the patients in group B. Mortality was 0% in group B and 4.4% in the group A. Conclusion: The positive influence of HBO on the treatment of Fournier’s gangrene can be estimated only from the available data. Despite poorer baseline findings with comparable risk factors, mortality was 0% in the HBO group. The analysis of a larger patient cohort is desirable to increase the significance of the results.
Background: Magnetic resonance imaging (MRI) techniques are rarely used in the context of abdominal sepsis and in sepsis research. This study investigates the impact of MRI for monitoring septic peritonitis in an animal model (colon ascendens stent-induced peritonitis, CASP). The CASP model closely mimics that of human disease and is highly standardized. The most frequently employed readout parameter in mouse CASP studies is prolonged or decreased rate of survival. Monitoring the progression of peritonitis via MRI could provide a helpful tool in the evaluation of severity. The use of alternative readout systems could very well reduce the number of research animals. Perspectively, clinical improvement after certain treatment could be classified. Methods: This study describes for the first time MRI findings following the induction of septic peritonitis in mice using the CASP model. Two sublethal groups of mice with septic peritonitis were investigated. Each had received one of two differing stent diameters in order to control the leakage of feces into the abdominal cavity. Each mouse served as its own control. Imaging and analyses were performed blinded. Gut diameters, stomach volume, abdominal organ wall diameters, and volume of the adrenal glands were measured. Serum corticosterone levels were detected using ELISA. Serum IL-6, TNF-α, IL-1β, and IL-10 levels were screened by cytometric bead array. Statistical analysis was performed using the Mann-Whitney U test for nonparametric probes and the Kruskal-Wallis and t tests. Results: Using a 7-tesla MRI scanner 24 and 48 h after induction of septic peritonitis, interenteric fluid, organ swelling of spleen and adrenal glands, as well as dilatation of the stomach were compared to nonseptic conditions. Swelling of adrenal glands resulted in an increased serum corticosterone level. In addition, the wall of the intestine bowel was thickened. Based upon these findings, an MRI score (MRI sepsis score, MSS) for abdominal sepsis in mice was established. Reduced stent sizes led to reduced severity of the abdominal sepsis, which could be reproduced in the MSS, which is described here for the first time. Conclusions: Intraabdominal variations during septic peritonitis are detectable by MRI techniques. MRI methods should become a more important tool for the evaluation of abdominal peritonitis. MSS could provide an interesting tool for the evaluation of therapeutic strategies.
Significance of Hyperbaric Oxygenation in the Treatment of Fournier’s Gangrene: A Comparative Study
(2018)
Introduction: Hyperbaric oxygenation (HBO), in addition to anti-infective and surgical therapy, seems to be a key treatment point for Fournier’s gangrene. The aim of this study was to investigate the influence of HBO therapy on the outcome and prognosis of Fournier’s gangrene. Patients and Methods: In the present multicenter, retrospective observational study, we evaluated the data of approximately 62 patients diagnosed with Fournier’s gangrene between 2007 and 2017. For comparison, 2 groups were distinguished: patients without HBO therapy (group A, n = 45) and patients with HBO therapy (group B, n = 17). The analysis included sex, age, comorbidities, clinical symptoms, laboratory and microbiological data, debridement frequency, wound dressing, antibiotic use, outcome and prognosis. The statistical analysis was performed with GraphPad Prism 7® (GraphPad Software, Inc., La Jolla, USA). Results: Demographic data showed no significant differences. The laboratory parameters C-reactive protein and urea were significantly higher in group B (group B: 301.7 vs. 140.6 mg/dL; group A: 124.8 vs. 54.7 mg/dL). Sepsis criteria were fulfilled in 77.8 and 100% of the patients in groups A and B respectively. Treatment in the intensive care unit (ICU) was therefore indicated in 69% of the patients in group A and 100% of the patients in group B. The mean ICU stay was 9 and 32 days for patients in groups A and B respectively. The wound debridement frequency and hospitalization stay were significantly greater in group B (13 vs. 5 debridement and 40 vs. 22 days). Initial antibiosis was test validated in 80% of the patients in group A and 76.5% of the patients in group B. Mortality was 0% in group B and 4.4% in the group A. Conclusion: The positive influence of HBO on the treatment of Fournier’s gangrene can be estimated only from the available data. Despite poorer baseline findings with comparable risk factors, mortality was 0% in the HBO group. The analysis of a larger patient cohort is desirable to increase the significance of the results.
Background: Depression and obesity are widespread and closely linked. Brain-derived neurotrophic factor (BDNF) and vitamin D are both assumed to be associated with depression and obesity. Little is known about the interplay between vitamin D and BDNF. We explored the putative associations and interactions between serum BDNF and vitamin D levels with depressive symptoms and abdominal obesity in a large population-based cohort. Methods: Data were obtained from the population-based Study of Health in Pomerania (SHIP)-Trend (n = 3,926). The associations of serum BDNF and vitamin D levels with depressive symptoms (measured using the Patient Health Questionnaire) were assessed with binary and multinomial logistic regression models. The associations of serum BDNF and vitamin D levels with obesity (measured by the waist-to-hip ratio [WHR]) were assessed with binary logistic and linear regression models with restricted cubic splines. Results: Logistic regression models revealed inverse associations of vitamin D with depression (OR = 0.966; 95% CI 0.951–0.981) and obesity (OR = 0.976; 95% CI 0.967–0.985). No linear association of serum BDNF with depression or obesity was found. However, linear regression models revealed a U-shaped association of BDNF with WHR (p < 0.001). Conclusion: Vitamin D was inversely associated with depression and obesity. BDNF was associated with abdominal obesity, but not with depression. At the population level, our results support the relevant roles of vitamin D and BDNF in mental and physical health-related outcomes.
Background: Magnetic resonance imaging (MRI) techniques are rarely used in the context of abdominal sepsis and in sepsis research. This study investigates the impact of MRI for monitoring septic peritonitis in an animal model (colon ascendens stent-induced peritonitis, CASP). The CASP model closely mimics that of human disease and is highly standardized. The most frequently employed readout parameter in mouse CASP studies is prolonged or decreased rate of survival. Monitoring the progression of peritonitis via MRI could provide a helpful tool in the evaluation of severity. The use of alternative readout systems could very well reduce the number of research animals. Perspectively, clinical improvement after certain treatment could be classified. Methods: This study describes for the first time MRI findings following the induction of septic peritonitis in mice using the CASP model. Two sublethal groups of mice with septic peritonitis were investigated. Each had received one of two differing stent diameters in order to control the leakage of feces into the abdominal cavity. Each mouse served as its own control. Imaging and analyses were performed blinded. Gut diameters, stomach volume, abdominal organ wall diameters, and volume of the adrenal glands were measured. Serum corticosterone levels were detected using ELISA. Serum IL-6, TNF-α, IL-1β, and IL-10 levels were screened by cytometric bead array. Statistical analysis was performed using the Mann-Whitney U test for nonparametric probes and the Kruskal-Wallis and t tests. Results: Using a 7-tesla MRI scanner 24 and 48 h after induction of septic peritonitis, interenteric fluid, organ swelling of spleen and adrenal glands, as well as dilatation of the stomach were compared to nonseptic conditions. Swelling of adrenal glands resulted in an increased serum corticosterone level. In addition, the wall of the intestine bowel was thickened. Based upon these findings, an MRI score (MRI sepsis score, MSS) for abdominal sepsis in mice was established. Reduced stent sizes led to reduced severity of the abdominal sepsis, which could be reproduced in the MSS, which is described here for the first time. Conclusions: Intraabdominal variations during septic peritonitis are detectable by MRI techniques. MRI methods should become a more important tool for the evaluation of abdominal peritonitis. MSS could provide an interesting tool for the evaluation of therapeutic strategies.
Three-year-olds and 4-year-olds have severe difficulties solving standard mental rotation tasks. Only 5-year-olds solve such tasks above chance reliably. In contrast studies relying on simplified mental rotation tasks indicate that infants discriminate between an object and its mirror image. Furthermore in another simplified mental rotation task with 3-year-olds, a linear relation between angular disparity and reaction time typical for mental rotation was revealed. Therefore it was assumed that 3-year-olds’ capabilities are underestimated. In the current study, 3-year-olds were trained in two isolated sessions to solve standard mental rotation tasks and were tested in a third session. Three-year-olds solved this test above chance as a group – a substantial number of them doing so on an individual level. However, a linear relation between angular disparity and reaction time, that would indicate an analog mental transformation, was not discernable. Nevertheless, these findings are in accordance with a continuous line describing mental rotation in infants and older children. And, these also indicate that children’s mental rotation capabilities might be underestimated.
The social context plays a decisive role in the formation of the academic self-concept (ASC) and has been widely studied as the big-fish-little-pond-effect (BFLPE). This effect describes that comparable talented students in high-achieving school settings have a lower ASC compared to equally talented students attending low-achieving settings. Past research has focused on students’ domain-specific ASC, while little is known about the relation of achievement-related classroom compositions and the various facets of ASC. Additionally, BFLPE-research has been critiqued to build its theoretical frame on social comparison theory, without providing sufficient empirical support. To address this gap, we analyzed how the single student’s social, criterial, absolute, and individual ASC relate to class-level achievement of 8th graders. Applying Multilevel Structural Equation Modeling (MLSEM) we found that all facets of ASC were significantly related to average-class achievement, while student’s social ASC revealed the strongest associated. The results reveal explicitly that average-class achievement is strongly related to social comparison processes.
In the present study, we investigated whether inter-individual differences in vagally mediated heart rate variability (vmHRV) would be associated with inter-individual differences in empathy and alexithymia. To this end, we determined resting state HF-HRV in 90 individuals that also completed questionnaires assessing inter-individual differences in empathy and alexithymia. Our categorical and dimensional analyses revealed that inter-individual differences in HF-HRV were differently associated with inter-individual differences in empathy and alexithymia. We found that individuals with high HF-HRV reported more empathy and less alexithymia than individuals with low HF-HRV. Moreover, we even found that an increase in HF-HRV was associated with an increase in empathy and a decrease in alexithymia across all participants. Taken together, these findings indicate that individuals with high HF-HRV are more empathetic and less alexithymic than individuals with low HF-HRV. These differences in empathy and alexithymia may explain why individuals with high HF-HRV are more successful in sharing and understanding the mental and emotional states of others than individuals with low HF-HRV.
Medical education research has focused almost entirely on the education of future physicians. In comparison, findings on other health-related occupations, such as medical assistants, are scarce. With the current study, we wanted to examine the knowledge-is-power hypothesis in a real life educational setting and add to the sparse literature on medical assistants. Acquisition of vocational knowledge in vocational education and training (VET) was examined for medical assistant students (n = 448). Differences in domain-specific vocational knowledge were predicted by crystallized and fluid intelligence in the course of VET. A multiple matrix design with 3 year-specific booklets was used for the vocational knowledge tests of the medical assistants. The unique and joint contributions of the predictors were investigated with structural equation modeling. Crystallized intelligence emerged as the strongest predictor of vocational knowledge at every stage of VET, while fluid intelligence only showed weak effects. The present results support the knowledge-is-power hypothesis, even in a broad and more naturalistic setting. This emphasizes the relevance of general knowledge for occupations, such as medical assistants, which are more focused on learning hands-on skills than the acquisition of academic knowledge.
Tree growth at northern boreal treelines is generally limited by summer temperature, hence tree rings serve as natural archives of past climatic conditions. However, there is increasing evidence that a changing summer climate as well as certain micro-site conditions can lead to a weakening or loss of the summer temperature signal in trees growing in treeline environments. This phenomenon poses a challenge to all applications relying on stable temperature-growth relationships such as temperature reconstructions and dynamic vegetation models. We tested the effect of differing ecological and climatological conditions on the summer temperature signal of Scots pine at its northern distribution limits by analyzing twelve sites distributed along a 2200 km gradient from Finland to Western Siberia (Russia). Two frequently used proxies in dendroclimatology, ring width and maximum latewood density, were correlated with summer temperature for the period 1901–2013 separately for (i) dry vs. wet micro-sites and (ii) years with dry/warm vs. wet/cold climate regimes prevailing during the growing season. Differing climate regimes significantly affected the temperature signal of Scots pine at about half of our sites: While correlations were stronger in wet/cold than in dry/warm years at most sites located in Russia, differing climate regimes had only little effect at Finnish sites. Both tree-ring proxies were affected in a similar way. Interestingly, micro-site differences significantly affected absolute tree growth, but had only minor effects on the climatic signal at our sites. We conclude that, despite the treeline-proximal location, growth-limiting conditions seem to be exceeded in dry/warm years at most Russian sites, leading to a weakening or loss of the summer temperature signal in Scots pine here. With projected temperature increase, unstable summer temperature signals in Scots pine tree rings might become more frequent, possibly affecting dendroclimatological applications and related fields.
Submerged macrophytes play a key role in north temperate shallow lakes by stabilizing clear-water conditions. Eutrophication has resulted in macrophyte loss and shifts to turbid conditions in many lakes. Considerable efforts have been devoted to shallow lake restoration in many countries, but long-term success depends on a stable recovery of submerged macrophytes. However, recovery patterns vary widely and remain to be fully understood. We hypothesize that reduced external nutrient loading leads to an intermediate recovery state with clear spring and turbid summer conditions similar to the pattern described for eutrophication. In contrast, lake internal restoration measures can result in transient clear-water conditions both in spring and summer and reversals to turbid conditions. Furthermore, we hypothesize that these contrasting restoration measures result in different macrophyte species composition, with added implications for seasonal dynamics due to differences in plant traits. To test these hypotheses, we analyzed data on water quality and submerged macrophytes from 49 north temperate shallow lakes that were in a turbid state and subjected to restoration measures. To study the dynamics of macrophytes during nutrient load reduction, we adapted the ecosystem model PCLake. Our survey and model simulations revealed the existence of an intermediate recovery state upon reduced external nutrient loading, characterized by spring clear-water phases and turbid summers, whereas internal lake restoration measures often resulted in clear-water conditions in spring and summer with returns to turbid conditions after some years. External and internal lake restoration measures resulted in different macrophyte communities. The intermediate recovery state following reduced nutrient loading is characterized by a few macrophyte species (mainly pondweeds) that can resist wave action allowing survival in shallow areas, germinate early in spring, have energy-rich vegetative propagules facilitating rapid initial growth and that can complete their life cycle by early summer. Later in the growing season these plants are, according to our simulations, outcompeted by periphyton, leading to late-summer phytoplankton blooms. Internal lake restoration measures often coincide with a rapid but transient colonization by hornworts, waterweeds or charophytes. Stable clear-water conditions and a diverse macrophyte flora only occurred decades after external nutrient load reduction or when measures were combined.
The obligate anaerobe, spore forming bacterium Clostridioides difficile (formerly Clostridium difficile) causes nosocomial and community acquired diarrhea often associated with antibiotic therapy. Major virulence factors of the bacterium are the two large clostridial toxins TcdA and TcdB. The production of both toxins was found strongly connected to the metabolism and the nutritional status of the growth environment. Here, we systematically investigated the changes of the gene regulatory, proteomic and metabolic networks of C. difficile 630Δerm underlying the adaptation to the non-growing state in the stationary phase. Integrated data from time-resolved transcriptome, proteome and metabolome investigations performed under defined growth conditions uncovered multiple adaptation strategies. Overall changes in the cellular processes included the downregulation of ribosome production, lipid metabolism, cold shock proteins, spermine biosynthesis, and glycolysis and in the later stages of riboflavin and coenzyme A (CoA) biosynthesis. In contrast, different chaperones, several fermentation pathways, and cysteine, serine, and pantothenate biosynthesis were found upregulated. Focusing on the Stickland amino acid fermentation and the central carbon metabolism, we discovered the ability of C. difficile to replenish its favored amino acid cysteine by a pathway starting from the glycolytic 3-phosphoglycerate via L-serine as intermediate. Following the growth course, the reductive equivalent pathways used were sequentially shifted from proline via leucine/phenylalanine to the central carbon metabolism first to butanoate fermentation and then further to lactate fermentation. The toxin production was found correlated mainly to fluxes of the central carbon metabolism. Toxin formation in the supernatant was detected when the flux changed from butanoate to lactate synthesis in the late stationary phase. The holistic view derived from the combination of transcriptome, proteome and metabolome data allowed us to uncover the major metabolic strategies that are used by the clostridial cells to maintain its cellular homeostasis and ensure survival under starvation conditions.
Background: Depression and obesity are widespread and closely linked. Brain-derived neurotrophic factor (BDNF) and vitamin D are both assumed to be associated with depression and obesity. Little is known about the interplay between vitamin D and BDNF. We explored the putative associations and interactions between serum BDNF and vitamin D levels with depressive symptoms and abdominal obesity in a large population-based cohort. Methods: Data were obtained from the population-based Study of Health in Pomerania (SHIP)-Trend (n = 3,926). The associations of serum BDNF and vitamin D levels with depressive symptoms (measured using the Patient Health Questionnaire) were assessed with binary and multinomial logistic regression models. The associations of serum BDNF and vitamin D levels with obesity (measured by the waist-to-hip ratio [WHR]) were assessed with binary logistic and linear regression models with restricted cubic splines. Results: Logistic regression models revealed inverse associations of vitamin D with depression (OR = 0.966; 95% CI 0.951–0.981) and obesity (OR = 0.976; 95% CI 0.967–0.985). No linear association of serum BDNF with depression or obesity was found. However, linear regression models revealed a U-shaped association of BDNF with WHR (p < 0.001). Conclusion: Vitamin D was inversely associated with depression and obesity. BDNF was associated with abdominal obesity, but not with depression. At the population level, our results support the relevant roles of vitamin D and BDNF in mental and physical health-related outcomes.
Aquaporins (AQPs) facilitate the transepithelial water flow involved in epithelial fluid secretion in numerous tissues; however, their function in the pancreas is less characterized. Acute pancreatitis (AP) is a serious disorder in which specific treatment is still not possible. Accumulating evidence indicate that decreased pancreatic ductal fluid secretion plays an essential role in AP; therefore, the aim of this study was to investigate the physiological and pathophysiological role of AQPs in the pancreas. Expression and localization of AQPs were investigated by real-time PCR and immunocytochemistry, whereas osmotic transmembrane water permeability was estimated by the dye dilution technique, in Capan-1 cells. The presence of AQP1 and CFTR in the mice and human pancreas were investigated by immunohistochemistry. Pancreatic ductal HCO3- and fluid secretion were studied on pancreatic ducts isolated from wild-type (WT) and AQP1 knock out (KO) mice using microfluorometry and videomicroscopy, respectively. In vivo pancreatic fluid secretion was estimated by magnetic resonance imaging. AP was induced by intraperitoneal injection of cerulein and disease severity was assessed by measuring biochemical and histological parameters. In the mice, the presence of AQP1 was detected throughout the whole plasma membrane of the ductal cells and its expression highly depends on the presence of CFTR Cl- channel. In contrast, the expression of AQP1 is mainly localized to the apical membrane of ductal cells in the human pancreas. Bile acid treatment dose- and time-dependently decreased mRNA and protein expression of AQP1 and reduced expression of this channel was also demonstrated in patients suffering from acute and chronic pancreatitis. HCO3- and fluid secretion significantly decreased in AQP1 KO versus WT mice and the absence of AQP1 also worsened the severity of pancreatitis. Our results suggest that AQP1 plays an essential role in pancreatic ductal fluid and HCO3- secretion and decreased expression of the channel alters fluid secretion which probably contribute to increased susceptibility of the pancreas to inflammation.
Mendelian randomization (MR) is a framework for assessing causal inference using cross-sectional data in combination with genetic information. This paper summarizes statistical methods commonly applied and strait forward to use for conducting MR analyses including those taking advantage of the rich dataset of SNP-trait associations that were revealed in the last decade through large-scale genome-wide association studies. Using these data, powerful MR studies are possible. However, the causal estimate may be biased in case the assumptions of MR are violated. The source and the type of this bias are described while providing a summary of the mathematical formulas that should help estimating the magnitude and direction of the potential bias depending on the specific research setting. Finally, methods for relaxing the assumptions and for conducting sensitivity analyses are discussed. Future researches in the field of MR include the assessment of non-linear causal effects, and automatic detection of invalid instruments.
Background: We aimed to update the 2010 evidence- and consensus-based national clinical guideline on the diagnosis and management of uncomplicated urinary tract infections (UTIs) in adult patients. Results are published in 2 parts. Part 1 covers methods, the definition of patient groups, and diagnostics. This second publication focuses on treatment of acute episodes of cystitis and pyelonephritis as well as on prophylaxis of recurrent UTIs. Materials and Methods: An interdisciplinary group consisting of 17 representatives of 12 medical societies and a patient representative was formed. Systematic literature searches were conducted in MEDLINE, EMBASE, and the Cochrane Library to identify literature published in 2010–2015. Results: For the treatment of acute uncomplicated cystitis (AUC), fosfomycin-trometamol, nitrofurantoin, nitroxoline, pivmecillinam, and trimethoprim (depending on the local rate of resistance) are all equally recommended. Cotrimoxazole, fluoroquinolones, and cephalosporins are not recommended as antibiotics of first choice, for concern of an unfavorable impact on the microbiome. Mild to moderate uncomplicated pyelonephritis should be treated with oral cefpodoxime, ceftibuten, ciprofloxacin, or levofloxacin. For AUC with mild to moderate symptoms, instead of antibiotics symptomatic treatment alone may be considered depending on patient preference after discussing adverse events and outcomes. Primarily non-antibiotic options are recommended for prophylaxis of recurrent urinary tract infection. Conclusion: In accordance with the global antibiotic stewardship initiative and considering new insights in scientific research, we updated our German clinical UTI guideline to promote a responsible antibiotic use and to give clear hands-on recommendations for the diagnosis and management of UTIs in adults in Germany for healthcare providers and patients.
Together with endothelial cells and the glomerular basement membrane, podocytes form the size-specific filtration barrier of the glomerulus with their interdigitating foot processes. Since glomerulopathies are associated with so-called foot process effacement—a severe change of well-formed foot processes into flat and broadened processes—visualization of the three-dimensional podocyte morphology is a crucial part for diagnosis of nephrotic diseases. However, interdigitating podocyte foot processes are too narrow to be resolved by classic light microscopy due to Ernst Abbe's law making electron microscopy necessary. Although three dimensional electron microscopy approaches like serial block face and focused ion beam scanning electron microscopy and electron tomography allow volumetric reconstruction of podocytes, these techniques are very time-consuming and too specialized for routine use or screening purposes. During the last few years, different super-resolution microscopic techniques were developed to overcome the optical resolution limit enabling new insights into podocyte morphology. Super-resolution microscopy approaches like three dimensional structured illumination microscopy (3D-SIM), stimulated emission depletion microscopy (STED) and localization microscopy [stochastic optical reconstruction microscopy (STORM), photoactivated localization microscopy (PALM)] reach resolutions down to 80–20 nm and can be used to image and further quantify podocyte foot process morphology. Furthermore, in vivo imaging of podocytes is essential to study the behavior of these cells in situ. Therefore, multiphoton laser microscopy was a breakthrough for in vivo studies of podocytes in transgenic animal models like rodents and zebrafish larvae because it allows imaging structures up to several hundred micrometer in depth within the tissue. Additionally, along with multiphoton microscopy, lightsheet microscopy is currently used to visualize larger tissue volumes and therefore image complete glomeruli in their native tissue context. Alongside plain visualization of cellular structures, atomic force microscopy has been used to study the change of mechanical properties of podocytes in diseased states which has been shown to be a culprit in podocyte maintenance. This review discusses recent advances in the field of microscopic imaging and demonstrates their currently used and other possible applications for podocyte research.
Action comprehension that is related to language or gestural integration has been shown to engage the motor system in the brain, thus providing preliminary evidence for the gestural-verbal embodiment concept. Based on the involvement of the sensorimotor cortex (M1) in language processing, we aimed to further explore its role in the cognitive embodiment necessary for gestural-verbal integration. As such, we applied anodal (excitatory) and sham transcranial direct current stimulation (tDCS) over the left M1 (with reference electrode over the contralateral supraorbital region) during a gestural-verbal integration task where subjects had to make a decision about the semantic congruency of the gesture (prime) and the word (target). We used a cross-over within-subject design in young subjects. Attentional load and simple reaction time (RT) tasks served as control conditions, applied during stimulation (order of three tasks was counterbalanced). Our results showed that anodal (atDCS) compared to sham tDCS (stDCS) reduced RTs in the gestural-verbal integration task, specifically for incongruent pairs of gestures and verbal expressions, with no effect on control task performance. Our findings provide evidence for the involvement of the sensorimotor system in gestural-verbal integration performance. Further, our results suggest that functional modulation induced by sensorimotor tDCS may be specific to gestural-verbal integration. Future studies should now evaluate the modulatory effect of tDCS on semantic congruency by using tDCS over additional brain regions and include assessments of neural connectivity.
Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood–brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds.
Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis
(2018)
Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function.
Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production.
Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression.
Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.
Background
The role of platelets for mediating closure of the ductus arteriosus in human preterm infants is controversial. Especially, the effect of low platelet counts on pharmacological treatment failure is still unclear.
Methods
In this retrospective study of 471 preterm infants [<1,500 g birth weight (BW)], who were treated for a patent ductus arteriosus (PDA) with indomethacin or ibuprofen, we investigated whether platelet counts before or during pharmacological treatment had an impact on the successful closure of a hemodynamically significant PDA. The effects of other factors, such as sepsis, preeclampsia, gestational age, BW, and gender, were also evaluated.
Results
Platelet counts before initiation of pharmacological PDA treatment did not differ between infants with later treatment success or failure. However, we found significant associations between low platelet counts during pharmacological PDA therapy and treatment failure (p < 0.05). Receiver operating characteristic (ROC) curve analysis showed that platelet counts after the first, and before and after the second cyclooxygenase inhibitor (COXI) cycle were significantly associated with treatment failure (area under the curve of >0.6). However, ROC curve analysis did not reveal a specific platelet cutoff-value that could predict PDA treatment failure. Multivariate logistic regression analysis showed that lower platelet counts, a lower BW, and preeclampsia were independently associated with COXI treatment failure.
Conclusion
We provide further evidence for an association between low platelet counts during pharmacological therapy for symptomatic PDA and treatment failure, while platelet counts before initiation of therapy did not affect treatment outcome.
Introduction
We retrospectively evaluated the efficacy and toxicity of gross tumor volume (GTV) mean dose optimized stereotactic body radiation therapy (SBRT) for primary and secondary lung tumors with and without robotic real-time motion compensation.
Materials and methods
Between 2011 and 2017, 208 patients were treated with SBRT for 111 primary lung tumors and 163 lung metastases with a median GTV of 8.2 cc (0.3–174.0 cc). Monte Carlo dose optimization was performed prioritizing GTV mean dose at the potential cost of planning target volume (PTV) coverage reduction while adhering to safe normal tissue constraints. The median GTV mean biological effective dose (BED)10 was 162.0 Gy10 (34.2–253.6 Gy10) and the prescribed PTV BED10 ranged 23.6–151.2 Gy10 (median, 100.8 Gy10). Motion compensation was realized through direct tracking (44.9%), fiducial tracking (4.4%), and internal target volume (ITV) concepts with small (≤5 mm, 33.2%) or large (>5 mm, 17.5%) motion. The local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity were analyzed.
Results
Median follow-up was 14.5 months (1–72 months). The 2-year actuarial LC, PFS, and OS rates were 93.1, 43.2, and 62.4%, and the median PFS and OS were 18.0 and 39.8 months, respectively. In univariate analysis, prior local irradiation (hazard ratio (HR) 0.18, confidence interval (CI) 0.05–0.63, p = 0.01), GTV/PTV (HR 1.01–1.02, CI 1.01–1.04, p < 0.02), and PTV prescription, mean GTV, and maximum plan BED10 (HR 0.97–0.99, CI 0.96–0.99, p < 0.01) were predictive for LC while the tracking method was not (p = 0.97). For PFS and OS, multivariate analysis showed Karnofsky Index (p < 0.01) and tumor stage (p ≤ 0.02) to be significant factors for outcome prediction. Late radiation pneumonitis or chronic rip fractures grade 1–2 were observed in 5.3% of the patients. Grade ≥3 side effects did not occur.
Conclusion
Robotic SBRT is a safe and effective treatment for lung tumors. Reducing the PTV prescription and keeping high GTV mean doses allowed the reduction of toxicity while maintaining high local tumor control. The use of real-time motion compensation is strongly advised, however, well-performed ITV motion compensation may be used alternatively when direct tracking is not feasible.
In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes. Simultaneously arising and misrepaired DNA double-strand breaks are also the cause of another phenomenon called chromoplexy, which is characterized by the presence of chained translocations and interlinking deletion bridges involving several chromosomes. In this study, we demonstrate the genome-wide identification of chromosomal translocations based on the analysis of translocation-associated changes in spatial proximities of chromosome territories on the example of the cutaneous T-cell lymphoma cell line Se-Ax. We have used alterations of intra- and interchromosomal interaction probabilities as detected by genome-wide chromosome conformation capture (Hi-C) to infer the presence of translocations and to fine-map their breakpoints. The outcome of this analysis was subsequently compared to datasets on DNA copy number alterations and gene expression. The presence of chained translocations within the Se-Ax genome, partly connected by intervening deletion bridges, indicates a role of chromoplexy in the etiology of this cutaneous T-cell lymphoma. Notably, translocation breakpoints were significantly overrepresented in genes, which highlight gene-associated biological processes like transcription or other gene characteristics as a possible cause of the observed complex rearrangements. Given the relevance of chromosomal aberrations for basic and translational research, genome-wide high-resolution analysis of structural chromosomal aberrations will gain increasing importance.
The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders—such as rubella, human immunodeficiency virus, and herpesviruses—and human distal-less homeobox (DLX) proteins expressed in developing brain—namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity—that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens.
Recent research suggests that the P3b may be closely related to the activation of the locus coeruleus-norepinephrine (LC-NE) system. To further study the potential association, we applied a novel technique, the non-invasive transcutaneous vagus nerve stimulation (tVNS), which is speculated to increase noradrenaline levels. Using a within-subject cross-over design, 20 healthy participants received continuous tVNS and sham stimulation on two consecutive days (stimulation counterbalanced across participants) while performing a visual oddball task. During stimulation, oval non-targets (standard), normal-head (easy) and rotated-head (difficult) targets, as well as novel stimuli (scenes) were presented. As an indirect marker of noradrenergic activation we also collected salivary alpha-amylase (sAA) before and after stimulation. Results showed larger P3b amplitudes for target, relative to standard stimuli, irrespective of stimulation condition. Exploratory post hoc analyses, however, revealed that, in comparison to standard stimuli, easy (but not difficult) targets produced larger P3b (but not P3a) amplitudes during active tVNS, compared to sham stimulation. For sAA levels, although main analyses did not show differential effects of stimulation, direct testing revealed that tVNS (but not sham stimulation) increased sAA levels after stimulation. Additionally, larger differences between tVNS and sham stimulation in P3b magnitudes for easy targets were associated with larger increase in sAA levels after tVNS, but not after sham stimulation. Despite preliminary evidence for a modulatory influence of tVNS on the P3b, which may be partly mediated by activation of the noradrenergic system, additional research in this field is clearly warranted. Future studies need to clarify whether tVNS also facilitates other processes, such as learning and memory, and whether tVNS can be used as therapeutic tool.
Arm Ability Training (AAT) has been specifically designed to promote manual dexterity recovery for stroke patients who have mild to moderate arm paresis. The motor control problems that these patients suffer from relate to a lack of efficiency in terms of the sensorimotor integration needed for dexterity. Various sensorimotor arm and hand abilities such as speed of selective movements, the capacity to make precise goal-directed arm movements, coordinated visually guided movements, steadiness, and finger dexterity all contribute to our “dexterity” in daily life. All these abilities are deficient in stroke patients who have mild to moderate paresis causing focal disability. The AAT explicitly and repetitively trains all these sensorimotor abilities at the individual's performance limit with eight different tasks; it further implements various task difficulty levels and integrates augmented feedback in the form of intermittent knowledge of results. The evidence from two randomized controlled trials indicates the clinical effectiveness of the AAT with regard to the promotion of “dexterity” recovery and the reduction of focal disability in stroke patients with mild to moderate arm paresis. In addition, the effects have been shown to be superior to time-equivalent “best conventional therapy.” Further, studies in healthy subjects showed that the AAT induced substantial sensorimotor learning. The observed learning dynamics indicate that different underlying sensorimotor arm and hand abilities are trained. Capacities strengthened by the training can, in part, be used by both arms. Non-invasive brain stimulation experiments and functional magnetic resonance imaging data documented that at an early stage in the training cortical sensorimotor network areas are involved in learning induced by the AAT, yet differentially for the tasks trained. With prolonged training over 2 to 3 weeks, subcortical structures seem to take over. While behavioral similarities in training responses have been observed in healthy volunteers and patients, training-induced functional re-organization in survivors of a subcortical stroke uniquely involved the ipsilesional premotor cortex as an adaptive recruitment of this secondary motor area. Thus, training-induced plasticity in healthy and brain-damaged subjects are not necessarily the same.
Background: Biomarkers for gains of evidence based interventions for upper limb motor training in the subacute stage following stroke have rarely been described. Information about these parameters might help to identify patients who benefit from specific interventions and to determine individually expected behavioral gains for a certain period of therapy.
Objective: To evaluate predictors for hand motor outcome after arm ability training in the subacute stage after stroke selected from known potentially relevant parameters (initial motor strength, structural integrity of the pyramidal tract and functional motor cortex integrity).
Methods: We applied the arm ability training (AAT) over 3 weeks to a subpopulation of stroke patients with mild arm paresis, i.e., in 14 patients on average 4 weeks after stroke. The following biomarkers were measured before therapy onset: grip strength on the affected hand, transcranial magnetic stimulation recruitment curve steepness over the primary motor hand area [slope ratio between the ipsilesional hemisphere (IH) and contralesional hemisphere (CH)], and diffusion weighted MRI fractional anisotropy (FA) in the posterior limb of the internal capsule (PLIC; determined as a lateralization index between IH and CH). Outcome was assessed as the AATgain (percentage improvement over training). The “Test d'Evaluation des Membres Supérieurs de Personnes Âgées” (TEMPA) was assessed before and after training to test for possible associations of AAT with activity of daily living.
Results: A stepwise linear regression identified the lateralization index of PLIC FA as the only significant predictor for AAT-gain (R2 = 0.519; P = 0.029). AAT-gain was positively associated (r = 0.59; P = 0.028) with improvement in arm function during daily activities (TEMPA).
Conclusions: While all mildly affected patients achieved a clinically relevant therapeutic effect, pyramidal tract integrity nevertheless had a modifying role for clinical benefit.
Do We Need to Rethink the Epidemiology and Healthcare Utilization of Parkinson's Disease in Germany?
(2018)
Epidemiological aspects of Parkinson's disease (PD), co-occurring diseases and medical healthcare utilization of PD patients are still largely elusive. Based on claims data of 3.7 million statutory insurance members in Germany in 2015 the prevalence and incidence of PD was determined. PD cases had at least one main hospital discharge diagnosis of PD, or one physician diagnosis confirmed by a subsequent or independent diagnosis or by PD medication in 2015. Prevalence of (co-)occurring diseases, mortality, and healthcare measures in PD cases and matched controls were compared. In 2015, 21,714 prevalent PD cases (standardized prevalence: 511.4/100,000 persons) and 3,541 incident PD cases (standardized incidence: 84.1/100,000 persons) were identified. Prevalence of several (co-)occurring diseases/complications, e.g., dementia (PD/controls: 39/13%), depression (45/22%), bladder dysfunction (46/22%), and diabetes (35/31%), as well as mortality (10.7/5.8%) differed between PD cases and controls. The annual healthcare utilization was increased in PD cases compared to controls, e.g., regarding mean ± SD physician contacts (15.2 ± 7.6/12.2 ± 7.3), hospitalizations (1.3 ± 1.8/0.7 ± 1.4), drug prescriptions (overall: 37.7 ± 24.2/21.7 ± 19.6; anti-PD medication: 7.4 ± 7.4/0.1 ± 0.7), assistive/therapeutic devices (47/30%), and therapeutic remedies (57/16%). The standardized prevalence and incidence of PD in Germany as well as mortality in PD may be substantially higher than reported previously. While frequently diagnosed with co-occurring diseases/complications, such as dementia, depression, bladder dysfunction and diabetes, the degree of healthcare utilization shows large variability between PD patients. These findings encourage a rethinking of the epidemiology and healthcare utilization in PD, at least in Germany. Longitudinal studies of insurance claims data should further investigate the individual and epidemiological progression and healthcare demands in PD.
Objectives: We aimed to update the 2010 evidence- and consensus-based national clinical guideline on the diagnosis and management of uncomplicated urinary tract infections (UTIs) in adult patients. Materials and Methods: An interdisciplinary group consisting of 17 representatives of 12 medical societies and a patient representative was formed. Systematic literature searches were conducted in MEDLINE, EMBASE, and the Cochrane Library to identify literature published in 2010–2015. Results: We provide 75 recommendations and 68 statements in the updated evidence- and consensus-based national clinical guideline. The diagnostics part covers practical recommendations on cystitis and pyelonephritis for each defined patient group. Clinical examinations, as well as laboratory testing and microbiological pathogen assessment, are addressed. Conclusion: In accordance with the global antibiotic stewardship initiative and considering new insights in scientific research, we updated our German clinical UTI guideline to promote a responsible antibiotic use and to give clear hands-on recommendations for the diagnosis and management of UTIs in adults in Germany for healthcare providers and patients.
Objective: To evaluate the efficacy and tolerability of brivaracetam (BRV) in a severely drug refractory cohort of patients with epileptic encephalopathies (EE).
Method: A multicenter, retrospective cohort study recruiting all patients treated with EE who began treatment with BRV in an enrolling epilepsy center between 2016 and 2017.
Results: Forty-four patients (27 male [61%], mean age 29 years, range 6 to 62) were treated with BRV. The retention rate was 65% at 3 months, 52% at 6 months and 41% at 12 months. A mean retention time of 5 months resulted in a cumulative exposure to BRV of 310 months. Three patients were seizure free during the baseline. At 3 months, 20 (45%, 20/44 as per intention-to-treat analysis considering all patients that started BRV including three who were seizure free during baseline) were either seizure free (n = 4; 9%, three of them already seizure-free at baseline) or reported at least 25% (n = 4; 9%) or 50% (n = 12; 27%) reduction in seizures. An increase in seizure frequency was reported in two (5%) patients, while there was no change in the seizure frequency of the other patients. A 50% long-term responder rate was apparent in 19 patients (43%), with two (5%) free from seizures for more than six months and in nine patients (20%, with one [2 %] free from seizures) for more than 12 months. Treatment-emergent adverse events were predominantly of psychobehavioural nature and were observed in 16%.
Significance: In this retrospective analysis the rate of patients with a 50% seizure reduction under BRV proofed to be similar to those seen in regulatory trials for focal epilepsies. BRV appears to be safe and relatively well tolerated in EE and might be considered in patients with psychobehavioral adverse events while on levetiracetam.
Mast cells reside on and near the cerebral vasculature, the predominant site of pneumococcal entry into the central nervous system (CNS). Although mast cells have been reported to be crucial in protecting from systemic bacterial infections, their role in bacterial infections of the CNS remained elusive. Here, we assessed the role of mast cells in pneumococcal infection in vitro and in vivo. In introductory experiments using mouse bone marrow-derived mast cells (BMMC), we found that (i) BMMC degranulate and release selected cytokines upon exposure to Streptococcus pneumoniae, (ii) the response of BMMC varies between different pneumococcal serotypes and (iii) is dependent on pneumolysin. Intriguingly though, apart from a slight enhancement of cerebrospinal fluid (CSF) pleocytosis, neither two different mast cell-deficient Kit mutant mouse strains (WBB6F1-KitW/Wv and C57BL/6 KitW-sh/W-sh mice) nor pharmacologic mast cell stabilization with cromoglycate had any significant impact on the disease phenotype of experimental pneumococcal meningitis. The incomplete reversal of the enhanced CSF pleocytosis by local mast cell engraftment suggests that this phenomenon is caused by other c-Kit mutation-related mechanisms than mast cell deficiency. In conclusion, our study suggests that mast cells can be activated by S. pneumoniae in vitro. However, mast cells do not play a significant role as sentinels of pneumococcal CSF invasion and initiators of innate immunity in vivo.
Species of the genus Wolffia are traditionally used as human food in some of the Asian countries. Therefore, all 11 species of this genus, identified by molecular barcoding, were investigated for ingredients relevant to human nutrition. The total protein content varied between 20 and 30% of the freeze-dry weight, the starch content between 10 and 20%, the fat content between 1 and 5%, and the fiber content was ~25%. The essential amino acid content was higher or close to the requirements of preschool-aged children according to standards of the World Health Organization. The fat content was low, but the fraction of polyunsaturated fatty acids was above 60% of total fat and the content of n-3 polyunsaturated fatty acids was higher than that of n-6 polyunsaturated fatty acids in most species. The content of macro- and microelements (minerals) not only depended on the cultivation conditions but also on the genetic background of the species. This holds true also for the content of tocopherols, several carotenoids and phytosterols in different species and even intraspecific, clonal differences were detected in Wolffia globosa and Wolffia arrhiza. Thus, the selection of suitable clones for further applications is important. Due to the very fast growth and the highest yield in most of the nutrients, Wolffia microscopica has a high potential for practical applications in human nutrition.
Background and Aims: Gastrointestinal stromal tumors (GISTs) are rare malignancies but the most common mesenchymal tumors of the digestive tract. Recent advances in diagnostic imaging and an increasing incidence will confront us more frequently with stromal tumors. This single center study aimed to characterize GIST patients in terms of tumor location, clinical presentation, metastasis formation, as well as associated secondary malignancies. Methods: In a retrospective study, 104 patients with a histologically confirmed diagnosis of GIST, collected between 1993 and 2011, were characterized for several clinical features. Results: The most common GIST location was the stomach (67.6%) followed by the small intestine (16.2%). Gastrointestinal bleeding (55.8%) and abdominal pain (38.5%) were the most frequently reported symptoms whereas about one-third of patients remained clinically asymptomatic (31.6%); 14.4% of patients had either synchronous or metachronous metastases and there was a significant prevalence also in the low risk group. The proportion of secondary malignant associated neoplasms was 31% in our GIST cohort, among which gastrointestinal, genitourinary tumors, and breast cancer were the most prevalent. Conclusion: There was a considerable risk for metastasis formation and the development of secondary neoplasias that should encourage discussion about the appropriate surveillance strategy after surgery for GIST.
Background: Iodine deficiency disorders (IDD) represent a global health threat to individuals and societies. IDD prevention programmes have been introduced in many parts of the world. However, challenges remain, particularly in Europe due to fragmentation and diversity of approaches that are not harmonized. Objectives: This review is dedicated to the public-health impact of IDD prevention programmes. It sums up experiences collected by the EUthyroid consortium so far and provides information on stakeholders that should be involved in actions directed to improve the impact of IDD prevention. Methods: A joint European database for combining registry-based outcome and monitoring data as well as tools for harmonizing study methods were established. Methods for analyzing thyroglobulin from a dried blood spot are available for assessing the iodine status in the general population and at-risk groups. Mother-child cohorts are used for in-depth analysis of the potential impact of mild-to-moderate iodine deficiency on the neurocognitive development of the offspring. A decision-analytic model has been developed to evaluate the long-term effectiveness and cost effectiveness of IDD prevention programmes. Results: EUthyroid has produced tools and infrastructure to improve the quality of IDD monitoring and follows a dissemination strategy targeting policymakers and the general public. There are tight connections to major stakeholders in the field of IDD monitoring and prevention. Conclusions: EUthyroid has taken steps towards achieving a euthyroid Europe. Our challenge is to inspire a greater sense of urgency in both policymakers and the wider public to address this remediable deficit caused by IDD.
Based on the latest gnomAD dataset, the prevalence of symptomatic hereditary cerebral cavernous malformations (CCMs) prone to cause epileptic seizures and stroke-like symptoms was re-evaluated in this review and calculated to be 1:5,400-1:6,200. Furthermore, state-of-the-art molecular genetic analyses of the known CCM loci are described which reach an almost 100% mutation detection rate for familial CCMs if whole genome sequencing is performed for seemingly mutation-negative families. An update on the spectrum of CCM1, CCM2, and CCM3 mutations demonstrates that deep-intronic mutations and submicroscopic copy-number neutral genomic rearrangements are rare. Finally, this review points to current guidelines on genetic counselling, neuroimaging, medical as well as neurosurgical treatment and highlights the formation of active patient organizations in various countries.
Background: Levels or fluctuations in the partial pressure of CO<sub>2</sub> (PCO<sub>2</sub>) may affect outcomes for extremely low birth weight infants. Objectives: In an exploratory analysis of a randomized trial, we hypothesized that the PCO<sub>2</sub> values achieved could be related to significant outcomes. Methods: On each treatment day, infants were divided into 4 groups: relative hypocapnia, normocapnia, hypercapnia, or fluctuating PCO<sub>2</sub>. Ultimate assignment to a group for the purpose of this analysis was made according to the group in which an infant spent the most days. Statistical analyses were performed with analysis of variance (ANOVA), the Kruskal-Wallis test, the χ<sup>2</sup> test, and the Fisher exact test as well as by multiple logistic regression. Results: Of the 359 infants, 57 were classified as hypocapnic, 230 as normocapnic, 70 as hypercapnic, and 2 as fluctuating PCO<sub>2</sub>. Hypercapnic infants had a higher average product of mean airway pressure and fraction of inspired oxygen (MAP × FiO<sub>2</sub>). For this group, mortality was higher, as was the likelihood of having moderate/severe bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and poorer neurodevelopment. Multiple logistic regression analyses showed an increased risk for BPD or death associated with birth weight (p < 0.001) and MAP × FiO<sub>2</sub> (p < 0.01). The incidence of adverse neurodevelopment was associated with birth weight (p < 0.001) and intraventricular hemorrhage (IVH; p < 0.01). Conclusions: Birth weight and respiratory morbidity, as measured by MAP × FiO<sub>2</sub>, were the most predictive of death or BPD and NEC, whereas poor neurodevelopmental outcome was associated with low birth weight and IVH. Univariate models also identified PCO<sub>2</sub>. Thus, hypercapnia seems to reflect greater disease severity, a likely contributor to differences in outcomes.
The glioblastoma multiforme (GBM) not only presents the most common tumor of the central nervous system in adults, it is also the most aggressive brain tumor. Although patients suffering from GBM standardly receive a combination of multiple treatments including surgery, radiotherapy and chemotherapy, its prognosis is still poor with a median survival time of only 12-15 months. Therefore, new and effective treatment methods are urgently needed.
A signaling molecule which is both involved in proliferation, migration and invasion of a broad range of healthy and malignant cells is the lipid mediator sphingosine-1-phosphate (S1P). Previous studies have confirmed that sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) is involved in the regulation of proliferation, invasion, metastasis, vascular maturation and angiogenesis of GBM cells, and is closely related to the occurrence and development of tumors. Thus, ACT-209905 (provided by Actelion Pharmaceuticals) as a selective S1PR1 modulator was applied to gain insights into the molecular processes activated by S1PR1 in GBM cells using two human (LN18, U87MG) and one murine (GL261) GBM cell line.
In our in vitro cell viability analyses, we found that ACT-209905 significantly reduced viability of LN18 cells in a concentration dependent manner. A combined administration of ACT-209905 with S1PR2 inhibitors (Compound 16, Compound 16ME – both provided by ONO Pharmaceuticals, and JTE-013 – commercially available) showed a stronger effect than the single administration demonstrating that both S1PR1 and S1PR2 are involved in growth of GBM cells and may interact with each other. Our results also demonstrated that ACT-209905 can induce apoptosis in GBM cells since caspase 3 activity was induced by the S1PR1 modulator which might therefore play an important role in inhibiting the proliferation of GBM cells. Further, we found a significant inhibitory effect of ACT-209905 on the migration and invasion of LN18 and U87MG GBM cells arguing for a participation of S1PR1 signaling in migration and invasion of GBM cells, too. Stimulation of S1P receptors results in the activation of several kinases such as AKT1 and ERK1/2, correspondingly our immunoblot analyses showed a strong activation of both kinases by S1P which was reduced by ACT-209905 in LN18 cells but not in GL261 cells suggesting that different pathways are activated by S1P in these GBM cell lines. Further studies have to be performed to clarify the role of AKT1 and ERK1/2 in the inhibitory effects of ACT-209905 on GBM proliferation, migration and invasion.
Currently, GBM stem cells are discussed as a reason for resistance against the radiochemotherapy and the recurrence of the tumor. Our immunoblot analyses showed that Nestin and CD133, two marker proteins for GBM stem cells, were higher expressed in GBM cells treated with ACT-209905 compared to control or S1P treated LN18 cells. Further investigations in the future might contribute to the elucidation of an involvement of the S1P receptors in the stem cell behavior of GBM cells. Paradoxically to the up-regulation of CD133 and Nestin by ACT-209905, treatment of LN18 stem-like neurospheres with ACT-209905 showed a significant cytotoxic effect of the compound which was even more pronounced in the stem-like neurosphere cells compared to the adherent parental LN18 cells.
Overall, the studies of this work improve our understanding of the complex mechanisms of S1P signaling in GBM cells and might drive the development of its pharmacological modulation as a new therapeutic principle in GBM. Furthermore, an extended knowledge about the molecular effects of ACT-209905 on GBM cells will broaden the understanding for possible future applications and clinical indications.
In aktuellen Studien aus den letzten Jahren mehren sich die Hinweise auf metabolische Einflüsse
von Osteocalcin. Neben dem Skelettsystem scheint besonders der Energiestoffwechsel,
speziell auf der Ebene der Distribution und des Verbrauchs von Glucose mit Osteocalcin
zu interagieren. In der vorliegenden Studie wurden Blutplasma- und Urinproben von 931
gesunden Probanden mittels Massenspektrometrie (Tandem-Massenspektroskopie mit vorgeschalteter
Flüssigkeitschromatographie) auf niedermolekulare Substanzen untersucht, um
dann auf systemische Effekte von Osteocalcin zu schließen. Diese Methodik erlaubt eine
breite Untersuchung von Wirkungen von Osteocalcin in allen Organsystemen, auch in jenen,
für die bisher noch keine Interaktionen mit Osteocalcin bekannt sind. Die Berechnung eines
ersten Modells zeigte viele Zusammenhänge. Diese waren jedoch stark durch die Nierenfunktion
beeinflusst. Nach Adjustierung für die Nierenfunktion blieben insgesamt 29 signifikante
Ergebnisse erhalten. Zu diesen Ergebnissen zählten zuvorderst Zwischenprodukte des
Kollagenstoffwechsels, besonders Prolinderivate, was die Bedeutung von Osteocalcin im
Knochenstoffwechsel unterstreicht. Die weiteren Ergebnisse umfassten eine Assoziation mit
Kynurenin, ein Hinweis auf die Möglichkeit, dass Entzündungen Einflüsse auf zirkulierendes
Osteocalcin haben könnten. Weitere Hinweise auf die bereits bekannte Verknüpfung zwischen
dem Energiestoffwechsel und Osteocalcin bietet die vorliegende Studie durch die Detektion
einer Assoziation zwischen Osteocalcin und Abbauprodukten von verzweigtkettigen
Aminosäuren. Auch scheint Osteocalcin vom Lebensstil, wie beispielsweise dem Tabakrauchen,
beeinflusst zu werden. Zusammenfassend bietet die vorliegende Studie einen umfassenden
Überblick über die metabolischen Einflüsse von Osteocalcin. Darin war eine Vielzahl
von Assoziationen nachweisbar, die jedoch insgesamt für eine eher geringe Rolle von Osteocalcin
im menschlichen Stoffwechsel sprechen.
GH und sein Hauptmediator IGF-I spielen eine wichtige Rolle im Knochenstoffwechsel. Der Zusammenhang zwischen IGF-I und verminderter BMD bei Osteoporose wurde bereits vielfach untersucht. Insbesondere in Bezug auf eine mögliche geschlechtsspezifische Assoziation wurden allerdings widersprüchliche Ergebnisse gefunden. Zudem gibt es wenige Daten zu QUS-Messungen zur Bestimmung der Knochenqualität und zum IGFBP-3, welches die Bioverfügbarkeit von IGF-I reguliert. Das Ziel der vorliegenden Arbeit war daher, diese Zusammenhänge in der Allgemeinbevölkerung im Nordosten Deutschlands zu untersuchten. Grundlage für die Analysen der vorliegenden Studie bildeten die Daten von 3.543 Teilnehmern (1.759 Männer und 1.784 Frauen im Alter von 20-79 Jahren) von SHIP-Trend, einer bevölkerungsbasierten Studie in der Region Vorpommern. Von allen diesen Probanden lagen Serum IGF-I und IGFBP-3 Werte ebenso wie Messwerte einer Quantitativen Ultraschallmessung am Calcaneus vor. Geschlechtsspezifische lineare und logistische Regressionsanalysen, adjustiert für Alter, Taillenumfang, Sport, Diabetes mellitus, hsCRP und Menopausenstatus (nur bei Frauen) wurden berechnet. Bei Männern wurden positive lineare Assoziationen zwischen IGF-I, der IGF-I/IGFBP-3 Ratio und den QUS Parametern SOS, BUA und dem Steifigkeitsindex beobachtet, während bei Frauen keine klaren, statistisch signifikanten Assoziationen gezeigt werden konnten. Weiterhin wurde in der logistischen Regressionsanalyse eine inverse Assoziation zwischen den IGF-I-Spiegeln und dem Risiko für eine osteoporotische Fraktur bei beiden Geschlechtern gefunden. Bei Männern konnte nach dem Abfall des IGF-I-Spiegels um eine SD eine um 18% erhöhte Wahrscheinlichkeit für ein mittleres Frakturrisiko, sowie eine um 37% höhere Wahrscheinlichkeit für ein hohes (gegenüber einem niedrigen) Frakturrisiko festgestellt werden. Bei Frauen stieg beim Absinken des IGF-I Spiegels um eine SD die Wahrscheinlichkeit für ein hohes (gegenüber einem niedrigen) osteoporotisches Frakturrisiko um 45%. Für das IGFBP-3 konnten keine Assoziationen mit den QUS Parametern oder dem Risiko für eine osteoporotische Fraktur bei beiden Geschlechtern gezeigt werden.
Insbesondere bei Männer bleibt Osteoporose oft unentdeckt. Die hier aufgezeigten Assoziationen von IGF-I mit dem Steifigkeitsindex und dem QUS-basierten Frakturrisiko könnten helfen, die Anzahl der nicht diagnostizierten Patienten mit Osteoporose, besonders bei Männern, zu senken.
Hintergrund und Ziele:
Nach Schätzung des Bundesamtes für Strahlenschutz erhielt in Deutschland im Jahr 2012 jeder Einwohner ca. 1,6 Röntgenuntersuchungen bzw. eine Strahlendosis von 1,8 mSv. Etwa ein Drittel aller Untersuchungen entfiel dabei auf den Skelettapparat. Auch die Hüftdiagnostik wird bisher primär anhand konventioneller Röntgen- oder CT-Bilder durchgeführt. Daher existieren bislang nur hierfür validierte Norm- und Referenzwerte. Da in Deutschland inzwischen fast flächendeckend die Option einer Diagnostik über die Magnetresonanztomographie (MRT) vorhanden ist, besteht die Möglichkeit, Patienten ohne Strahlenbelastung zu untersuchen. Das Ziel der vorliegenden Arbeit ist es daher eine wissenschaftliche Grundlage zur Auswertung von MRT-Bildern der Hüfte zu schaffen.
Methodik:
Zur Referenzwertbestimmung wurden der Center-Edge-Winkel (CE), der Centrum-Collum-Diaphysen-Winkel (CCD), der modifizierte Alpha-Winkel (AA), der Trianguläre Index (TI) und der Femurkopfdurchmesser (HD) an 3.226 coronalen MRT-Bildern (1.587 Männer, 1.639 Frauen) der SHIP-Studie untersucht. Des Weiteren wurden Abhängigkeiten der Winkel untereinander sowie zu somatometrischen Daten (Geschlecht, Alter, BMI, Körpergewicht, Körpergröße und Taillenumfang) analysiert. Aufgrund dieser Abhängigkeiten konnten zudem adjustierte Referenzwerte ermittelt werden. Zusätzlich wurden die Prävalenzen verschiedener Schwellenwertüberschreitungen in der Region Vorpommern bestimmt.
Ergebnisse:
Die Readerzertifizierung wurde anhand von 25 MRT-Datensätzen durchgeführt. Die nach der Bland-Altman-Methode bestimmten Qualitätsanforderungen an die Intra- und Interreader-Reliabilität wurden erfüllt.
Der aus den Messungen ermittelte durchschnittliche CE lag bei 31,1 Grad (± 7,02), der abgeleitete Normbereich, entsprechend dem 95 %-Referenzbereich (Mittelwert ± 1,96 * SD), bei 17,6 – 44,9 Grad. Für den CCD ergab sich ein Mittelwert von 126,9 Grad (± 6,66), der abgeleitete Normbereich betrug 113,9 – 140,0 Grad. Beim modifizierten AA wurde ein mittlerer Wert von 54,5 Grad (± 8,15) sowie ein Referenzbereich von 38,5 – 70,5 Grad gefunden. Im Mittel konnte für den TI -2,29 mm (± 0,667) errechnet werden, der HD betrug durchschnittlich 44,6 mm (± 3,94).
Unter den gemessenen Hüftparametern fanden sich, außer zwischen CE und AA bzw. TI sowie zwischen HD und CCE bzw. TI, auffällige Zusammenhänge. Die dabei ermittelten Effekte zwischen den Winkeln waren jedoch überwiegend geringer als die von somatometrischen Parametern. Hierbei waren die Effekte von Geschlecht und Alter auf die ermittelten Hüftparameter am größten. Deshalb wurden für CE, CCD und AA darauf adjustierte Referenzwerte ermittelt.
Die hier ermittelten Prävalenzen der Schwellenwertüberschreitungen umfassen einen großen Bereich, da derzeit unterschiedlichste Schwellenwerte Anwendung finden.
Schlussfolgerung:
In der Hüftdiagnostik an MRT-Daten können der CE, der CCD, der modifizierte AA, der TI, und der HD verlässlich bestimmt werden. Die hier ermittelten Messwerte der MRT-Diagnostik stimmen im Wesentlichen mit den etablierten Normwerten der röntgenologischen und computertomographischen Bildgebung überein. Die erwarteten Abhängigkeiten der ermittelten Parameter untereinander sowie mit somatometrischen Parametern sind zum großen Teil gegeben. Zur genaueren Interpretation der Werte sollte aufgrund der Abhängigkeiten adjustierte Referenzwerte verwendet werden. Die Ergebnisse gelten für eine norddeutsche Population. Für allgemeingültige Normwerte sollte die Bevölkerung weiterer Regionen und Ethnien untersucht werden.
Das klinische Bild der Sepsis, des septischen Schockes und des Multiorganversagens sind nach wie vor Krankheitsbilder, wie sie auf Intensivstationen vorzufinden sind und häufig mit einer hohen Letalität assoziiert sind. Die Störung bzw. das Versagen der Mikrozirkulation ist und bleibt einer der Hauptmechanismen als Ursache dafür [1]. Die Zielsetzung der vorliegenden Arbeit war es, einen auf Zellebene beschriebenen Weg auf ein in vivo Tiermodell zu übertragen. Der bereits beschriebene Weg besagt, dass die Hemmung der Src-Tyrosinkinase durch das synthetische PP2, eine Reduktion der proinflammatorischen Zytokine zur Folge hat. Dieses sollte die Mikrozirkulation verbessern. In der vorliegenden Versuchsreihe wurde dafür ein bereits gut etablierter Versuchsablauf der experimentellen Endotoxinämie mit anschließender Intravitalmikroskopie am Tiermodell Ratte verwendet
In der vorliegenden Arbeit hat sich gezeigt, dass sich unter experimenteller Endotoxinämie sowie unter der Verwendung von PP2 bei einer Dosierung von 0,2mg/kg KG, die Mikrozirkulation signifikant verschlechtert. Dies wird bei Betrachtung der funktionellen Kapillardichten besonders deutlich. Im Vergleich der beiden endotoxiämischen Gruppen kann bei der Gruppe, die PP2 erhalten hat, ein Abfall der FCD von 47,8% für die Lamina longitudinalis und 25,5% für die Lamina circularis zu der Gruppe, die kein PP2 erhalten hat, festgestellt werden. Folglich ist es umgekehrt bei der Betrachtung der DFCD. Hierbei kann bei der Gruppe, welche LPS und PP2 erhalten hat, ein Anstieg von 30,27% für die Lamina longitudinalis bzw. 28,2% für die Lamina circularis, im Vergleich zu der Gruppe, der nur LPS appliziert wurde, beobachtet werden. In Bezug auf die NFCD zeigt sich ebenfalls ein Anstieg bei der Gruppe, die LPS und PP2 erhalten hat, jedoch ist dieser nicht signifikant.
Zudem zeigt sich eine Steigerung der Leukozyteninteraktion bei Endotoxinämie und zusätzlicher Verwendung von PP2 in den postkapillären Venolen 1. und 3. Ordnung. Dabei zeigt sich ein Anstieg der Leukozyten mit temporärer Adhäsion von 112,9% bei Venolen 1. Ordnung und 95% bei Venolen 3. Ordnung. Allerdings befindet sich der Mittelwert in jeder Gruppe bei <10 Leukozyten im Beobachtungszeitraum. Bei der permanenten Leukozytenadhäsion hingegen können keine signifikanten Unterschiede bei der Verwendung von PP2 beobachtet werden. Weiterhin zeigte sich bei der Verwendung von PP2 ein signifikanter Anstieg der Lactatkonzentration von 16,35%, wenn zuvor LPS gegeben worden ist. In der Untersuchung der Zytokine zeigten sich Veränderungen zwischen den Gruppen mit und ohne Endotoxinämie. Die Verwendung von PP2 ist dabei irrelevant.
Anomalous Nernst effect and three-dimensional
temperature gradients in magnetic tunnel junctions
(2018)
A Metabolic Labeling Strategy for Relative Protein Quantification in Clostridioides difficile
(2018)
Juvenile Myoclonic Epilepsy Shows Potential Structural White Matter Abnormalities: A TBSS Study
(2018)
Mendelian randomization (MR) is a framework for assessing causal inference using cross-sectional data in combination with genetic information. This paper summarizes statistical methods commonly applied and strait forward to use for conducting MR analyses including those taking advantage of the rich dataset of SNP-trait associations that were revealed in the last decade through large-scale genome-wide association studies. Using these data, powerful MR studies are possible. However, the causal estimate may be biased in case the assumptions of MR are violated. The source and the type of this bias are described while providing a summary of the mathematical formulas that should help estimating the magnitude and direction of the potential bias depending on the specific research setting. Finally, methods for relaxing the assumptions and for conducting sensitivity analyses are discussed. Future researches in the field of MR include the assessment of non-linear causal effects, and automatic detection of invalid instruments.
Two decades of research indicate that visual processing is typically enhanced for items that are in the space near the hands (near-hand space). Enhanced attention and cognitive control have been thought to be responsible for the observed effects, amongst others. As accumulating experimental evidence and recent theories of dual-tasking suggest an involvement of cognitive control and attentional processes during dual tasking, dual-task performance may be modulated in the near-hand space. Therefore, we performed a series of three experiments that aimed to test if the near-hand space affects the shift between task-component processing in two visual-manual tasks. We applied a Psychological Refractory Period Paradigm (PRP) with varying stimulus-onset asynchrony (SOA) and manipulated stimulus-hand proximity by placing hands either on the side of a computer screen (near-hand condition) or on the lap (far-hand condition). In Experiment 1, Task 1 was a number categorization task (odd vs. even) and Task 2 was a letter categorization task (vowel vs. consonant). Stimulus presentation was spatially segregated with Stimulus 1 presented on the right side of the screen, appearing first and then Stimulus 2, presented on the left side of the screen, appearing second. In Experiment 2, we replaced Task 2 with a color categorization task (orange vs. blue). In Experiment 3, Stimulus 1 and Stimulus 2 were centrally presented as a single bivalent stimulus. The classic PRP effect was shown in all three experiments, with Task 2 performance declining at short SOA while Task 1 performance being relatively unaffected by task-overlap. In none of the three experiments did stimulus-hand proximity affect the size of the PRP effect. Our results indicate that the switching operation between two tasks in the PRP paradigm is neither optimized nor disturbed by being processed in near-hand space.
Quantitative reconstructions of past vegetation cover commonly require pollen productivity estimates (PPEs). PPEs are calibrated in extensive and rather cumbersome surface-sample studies, and are so far only available for selected regions. Moreover, it may be questioned whether present-day pollen-landcover relationships are valid for palaeo-situations. We here introduce the ROPES approach that simultaneously derives PPEs and mean plant abundances from single pollen records. ROPES requires pollen counts and pollen accumulation rates (PARs, grains cm−2 year−1). Pollen counts are used to reconstruct plant abundances following the REVEALS approach. The principle of ROPES is that changes in plant abundance are linearly represented in observed PAR values. For example, if the PAR of pine doubles, so should the REVEALS reconstructed abundance of pine. Consequently, if a REVEALS reconstruction is “correct” (i.e., “correct” PPEs are used) the ratio “PAR over REVEALS” is constant for each taxon along all samples of a record. With incorrect PPEs, the ratio will instead vary. ROPES starts from random (likely incorrect) PPEs, but then adjusts them using an optimization algorithm with the aim to minimize variation in the “PAR over REVEALS” ratio across the record. ROPES thus simultaneously calculates mean plant abundances and PPEs. We illustrate the approach with test applications on nine synthetic pollen records. The results show that good performance of ROPES requires data sets with high underlying variation, many samples and low noise in the PAR data. ROPES can deliver first landcover reconstructions in regions for which PPEs are not yet available. The PPEs provided by ROPES may then allow for further REVEALS-based reconstructions. Similarly, ROPES can provide insight in pollen productivity during distinct periods of the past such as the Lateglacial. We see a potential to study spatial and temporal variation in pollen productivity for example in relation to site parameters, climate and land use. It may even be possible to detect expansion of non-pollen producing areas in a landscape. Overall, ROPES will help produce more accurate landcover reconstructions and expand reconstructions into new study regions and non-analog situations of the past. ROPES is available within the R package DISQOVER.
Intranasal Vaccination With Lipoproteins Confers Protection Against Pneumococcal Colonisation
(2018)
Streptococcus pneumoniae is endowed with a variety of surface-exposed proteins representing putative vaccine candidates. Lipoproteins are covalently anchored to the cell membrane and highly conserved among pneumococcal serotypes. Here, we evaluated these lipoproteins for their immunogenicity and protective potential against pneumococcal colonisation. A multiplex-based immunoproteomics approach revealed the immunogenicity of selected lipoproteins. High antibody titres were measured in sera from mice immunised with the lipoproteins MetQ, PnrA, PsaA, and DacB. An analysis of convalescent patient sera confirmed the immunogenicity of these lipoproteins. Examining the surface localisation and accessibility of the lipoproteins using flow cytometry indicated that PnrA and DacB were highly abundant on the surface of the bacteria. Mice were immunised intranasally with PnrA, DacB, and MetQ using cholera toxin subunit B (CTB) as an adjuvant, followed by an intranasal challenge with S. pneumoniae D39. PnrA protected the mice from pneumococcal colonisation. For the immunisation with DacB and MetQ, a trend in reducing the bacterial load could be observed, although this effect was not statistically significant. The reduction in bacterial colonisation was correlated with the increased production of antigen-specific IL-17A in the nasal cavity. Immunisation induced high systemic IgG levels with a predominance for the IgG1 isotype, except for DacB, where IgG levels were substantially lower compared to MetQ and PnrA. Our results indicate that lipoproteins are interesting targets for future vaccine strategies as they are highly conserved, abundant, and immunogenic.
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Platelets transfusion is a safe process, but during or after the process, the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). In this review, we focus on the inflammatory potential of platelet components (PCs) and their involvement in SARs. Recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses. Blood platelets are involved in inflammation and various other aspects of innate immunity through the release of a plethora of immunomodulatory cytokines, chemokines, and associated molecules, collectively termed biological response modifiers that behave like ligands for endothelial and leukocyte receptors and for platelets themselves. The involvement of PCs in SARs—particularly on a critically ill patient’s context—could be related, at least in part, to the inflammatory functions of platelets, acquired during storage lesions. Moreover, we focus on causal link between platelet activation and immune-mediated disorders (transfusion-associated immunomodulation, platelets, polyanions, and bacterial defense and alloimmunization). This is linked to the platelets’ propensity to be activated even in the absence of deliberate stimuli and to the occurrence of time-dependent storage lesions.
Human cytomegalovirus (HCMV) latency is typically harmless but reactivation can be largely detrimental to immune compromised hosts. We modeled latency and reactivation using a traceable HCMV laboratory strain expressing the Gaussia luciferase reporter gene (HCMV/GLuc) in order to interrogate the viral modulatory effects on the human adaptive immunity. Humanized mice with long-term (more than 17 weeks) steady human T and B cell immune reconstitutions were infected with HCMV/GLuc and 7 weeks later were further treated with granulocyte-colony stimulating factor (G-CSF) to induce viral reactivations. Whole body bio-luminescence imaging analyses clearly differentiated mice with latent viral infections vs. reactivations. Foci of vigorous viral reactivations were detectable in liver, lymph nodes and salivary glands. The number of viral genome copies in various tissues increased upon reactivations and were detectable in sorted human CD14+, CD169+, and CD34+ cells. Compared with non-infected controls, mice after infections and reactivations showed higher thymopoiesis, systemic expansion of Th, CTL, Treg, and Tfh cells and functional antiviral T cell responses. Latent infections promoted vast development of memory CD4+ T cells while reactivations triggered a shift toward effector T cells expressing PD-1. Further, reactivations prompted a marked development of B cells, maturation of IgG+ plasma cells, and HCMV-specific antibody responses. Multivariate statistical methods were employed using T and B cell immune phenotypic profiles obtained with cells from several tissues of individual mice. The data was used to identify combinations of markers that could predict an HCMV infection vs. reactivation status. In spleen, but not in lymph nodes, higher frequencies of effector CD4+ T cells expressing PD-1 were among the factors most suited to distinguish HCMV reactivations from infections. These results suggest a shift from a T cell dominated immune response during latent infections toward an exhausted T cell phenotype and active humoral immune response upon reactivations. In sum, this novel in vivo humanized model combined with advanced analyses highlights a dynamic system clearly specifying the immunological spatial signatures of HCMV latency and reactivations. These signatures can be merged as predictive biomarker clusters that can be applied in the clinical translation of new therapies for the control of HCMV reactivation.