Strenuous physical exercise induces monocyte chemoattractant protein-1 release in patients with coronary artery disease

Infiltration of the arterial vessel wall with monocytes is one of the initial inflammatory events. Monocyte chemoattractant protein-1 (MCP-1) is the key chemokine for the recruitment of monocytes to the atherosclerotic lesion. So far, it is unknown, if strenuous exercise enhances or reduces the release of MCP-1, the key initiator of pro-atherosclerotic inflammatory events in patients at risk for atherosclerotic diseases. 15 Patients with at least three coronary risk factors (CRF) like smoking, hypertension, diabetes, hypercholesterolemia and overweight and 17 corresponding healthy controls were tested with bicycle ergometry. Additionally, 8 patients with coronary artery disease (CAD) were investigated. Before and 10 minutes after maximal exercise, venous blood was taken and MCP-1 serum levels were analyzed. Furthermore, we measured monocyte CD11b expression by flow cytometry. Independently of CRF, the MCP-1 serum level was significantly increased after exercise. In control subjects the MCP-1 serum level rose from 71 pg/ml to 94 pg/ml (p<=0.05). In patients with CRF the MCP-1 serum level went up from 154 pg/ml to 224 pg/ml (p<=0.05). Patients with coronary artery disease had elevated MCP-1 serum levels before and after exercise, too, even if they did not have CRF (143 vs. 174 pg/ml; p<=0.05). The monocyte activation parameter CD11b showed a significant raise after physical exercise (relative fluorescence intensity 31 vs. 44; p<=0.05). These data indicate, that MCP-1 serum levels are elevated after physical exercise especially in patients at risk for coronary artery disease. These effects may in part result from an increased monocyte activation following strenuous physical exercise

Medienrezeption und Bewältigung - Studie in den Umfeldern des Literaturunterrichts der Jahrgangsstufe 6 einer Hauptschule

Die empirische Studie untersucht Medienrezeption von Hauptschülerinnen und Hauptschülern einer Jahrgangsstufe 6 vor dem Hintergrund ihrer psychosozialen Voraussetzungen und Dispositionen. Damit wird ein für die Didaktik des Faches Deutsch bisher weitgehend unbearbeitetes Feld – die Hauptschule – in das Zentrum des Interesses gerückt. Wesentliche Prozesse der Verarbeitung von Medien, die im Rahmen eines medienintegrativen Literaturunterrichts angeregt worden sind, werden herausgearbeitet und auf diverse Lebens- und Erfahrungshorizonte einer heterogenen Schülerschaft bezogen. Zentrale Einsicht der Studie ist, dass die untersuchten Hauptschülerinnen und Hauptschüler Mediengeschichten im Kontext ihrer z.T. prekären Lebensverhältnisse rezipieren und nutzen, so dass Rezeption letztlich nicht nur Bewältigung von Medieninhalten, sondern auch Bewältigung des eigenen Lebens bedeutet. Das gewählte Vorgehen ist explorativ und rekonstruktiv-interpretativ. Zunächst wird das Feld „Hauptschule“ und in Bezug auf den Deutschunterricht erörtert. Im Weiteren wird die aus der Interpretation der Daten hervorgehende übergeordnete Kategorie „ Bewältigung“ aus psychologischer, soziologischer sowie anthropologischer Perspektive diskutiert und mit drei interaktionistisch orientierten Ansätzen aus den Medienwirkungstheorien („Involvement“, „dynamisch-transaktionaler Ansatz“, „PKS-Modell“) in Verbindung gesetzt, so dass ein theoretischer Rahmen für die Interpretation der in zwei Fallarbeiten untersuchten Rezeptionsprozesse von Hauptschülerinnen und –schülern entsteht. In der „Fallarbeit 1 – Meidung und Rezeption“ tritt Bewältigung in der Kernkategorie „Meidung“ hervor. Hier werden auf der Basis der Grounded Theory unterschiedliche Typen eines Meidungsverhaltens mit Hilfe eines Datenschnitts, der alle Schülerinnen und Schüler der untersuchten Jahrgangsstufe 6 umfasst, abgegrenzt und als Rezeptionsoperationen der Schülerinnen und Schüler rekonstruiert. Die Daten wurden aus Medientagebüchern, die im Literaturunterricht entstanden sind, gewonnen. In der rekonstruktiven Arbeit an den Daten wird sichtbar, wie die Schülerinnen und Schüler sich trotz Angst erzeugender Impulse zu den Inhalten einer Mediengeschichte psychisch positionieren und rezeptive Bewältigungsstrategien (z.B. Verharmlosung, Distanzierung) entwerfen, um innere Balance zu wahren bzw. herzustellen. Die Dringlichkeit für die Schülerinnen und Schüler, auf diese Weise Mediengeschichten zu rezipieren, wird in der Fallarbeit 2 deutlich. Hier werden biographische und autobiographische Rekonstruktionen der Lebens- und Lernentwicklung in medienökologischer Absicht exemplarisch anhand von vier Fallbeispielen ausgearbeitet, um so die Hintergründe der Medienrezeption als Bewältigung aus den Kontexten der jeweiligen Lebens- und Alltagswelten zu erhellen. Dabei zeichnen sich die heterogenen Lebens- und Entwicklungsverhältnisse der Schülerinnen und Schüler (z.B. im Zusammenhang mit körperlichen Beeinträchtigungen, familiären Brüchen usw.) ab, die mehr oder weniger latent in das Rezeptionsverhalten einfließen. Die Studie richtet damit die fachdidaktische Perspektive des Faches Deutsch hinsichtlich eines medienintegrativen Literaturunterricht auf die hauptschulpädagogisch relevante Frage, welchen Beitrag die Literatur- und Mediendidaktik zur Lebensbewältigung von Hauptschülerinnen und – schülern unter Wahrung fachspezifischer Bildungsoptionen geben kann

The narrative self, distributed memory, and evocative objects

In this article, I outline various ways in which artifacts are interwoven with autobiographical memory systems and conceptualize what this implies for the self. I first sketch the narrative approach to the self, arguing that who we are as persons is essentially our (unfolding) life story, which, in turn, determines our present beliefs and desires, but also directs our future goals and actions. I then argue that our autobiographical memory is partly anchored in our embodied interactions with an ecology of artifacts in our environment. Lifelogs, photos, videos, journals, diaries, souvenirs, jewelry, books, works of art, and many other meaningful objects trigger and sometimes constitute emotionally-laden autobiographical memories. Autobiographical memory is thus distributed across embodied agents and various environmental structures. To defend this claim, I draw on and integrate distributed cognition theory and empirical research in human-technology interaction. Based on this, I conclude that the self is neither defined by psychological states realized by the brain nor by biological states realized by the organism, but should be seen as a distributed and relational construct

Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis

Platelets release preformed mediators and generate eicosanoids that regulate acute hemostasis and inflammation, but these anucleate cytoplasts are not thought to synthesize proteins or cytokines, or to influence inflammatory responses over time. Interrogation of an arrayed cDNA library demonstrated that quiescent platelets contain many messenger RNAs, one of which codes for interleukin 1β precursor (pro–IL-1β). Unexpectedly, the mRNA for IL-1β and many other transcripts are constitutively present in polysomes, providing a mechanism for rapid synthesis. Platelet activation induces rapid and sustained synthesis of pro–IL-1β protein, a response that is abolished by translational inhibitors. A portion of the IL-1β is shed in its mature form in membrane microvesicles, and induces adhesiveness of human endothelial cells for neutrophils. Signal-dependent synthesis of an active cytokine over several hours indicates that platelets may have previously unrecognized roles in inflammation and vascular injury. Inhibition of β3 integrin engagement markedly attenuated the synthesis of IL-1β, identifying a new link between the coagulation and inflammatory cascades, and suggesting that antithrombotic therapies may also have novel antiinflammatory effects

How non-native English-speaking staff are evaluated in linguistically diverse organizations: A sociolinguistic perspective

The aim of this paper is to examine the effects of evaluations of non-native speaking staff?s spoken English in international business settings. We adopt a sociolinguistic perspective on power and inequalities in linguistically diverse organizations in an Anglophone environment. The interpretive qualitative study draws on 54 interviews with non-native English-speaking staff in 19 UK business schools. We analyze, along the dimensions of status, solidarity and dynamism, the ways in which non-native speakers, on the basis of their spoken English, are evaluated by themselves and by listeners. We show how such evaluations refer to issues beyond the speaker?s linguistic fluency, and have consequences for her or his actions. The study contributes to the literature on language and power in international business through offering fine-grained insights into and elucidating how the interconnected evaluative processes impact the formation and perpetuation of organizational power relations and inequalities. It also puts forward implications for managing the officially monolingual, yet linguistically diverse organizations

Activated Polymorphonuclear Leukocytes Rapidly Synthesize Retinoic Acid Receptor-α: A Mechanism for Translational Control of Transcriptional Events

In addition to releasing preformed granular proteins, polymorphonuclear leukocytes (PMNs) synthesize chemokines and other factors under transcriptional control. Here we demonstrate that PMNs express an inducible transcriptional modulator by signal-dependent activation of specialized mechanisms that regulate messenger RNA (mRNA) translation. HL-60 myelocytic cells differentiated to surrogate PMNs respond to activation by platelet activating factor by initiating translation and with appearance of specific mRNA transcripts in polyribosomes. cDNA array analysis of the polyribosome fraction demonstrated that retinoic acid receptor (RAR)-α, a transcription factor that controls the expression of multiple genes, is one of the polyribosome-associated transcripts. Quiescent surrogate HL60 PMNs and primary human PMNs contain constitutive message for RAR-α but little or no protein. RAR-α protein is rapidly synthesized in response to platelet activating factor under the control of a specialized translational regulator, mammalian target of rapamycin, and is blocked by the therapeutic macrolide rapamycin, events consistent with features of the 5′ untranslated region of the transcript. Newly synthesized RAR-α modulates production of interleukin-8. Rapid expression of a transcription factor under translational control is a previously unrecognized mechanism in human PMNs that indicates unexpected diversity in gene regulation in this critical innate immune effector cell

Staphylococcus aureus α-Toxin Triggers the Synthesis of B-Cell Lymphoma 3 by Human Platelets

The frequency and severity of bacteremic infections has increased over the last decade and bacterial endovascular infections (i.e., sepsis or endocarditis) are associated with high morbidity and mortality. Bacteria or secreted bacterial products modulate platelet function and, as a result, affect platelet accumulation at sites of vascular infection and inflammation. However, whether bacterial products regulate synthetic events in platelets is not known. In the present study, we determined if prolonged contact with staphylococcal α-toxin signals platelets to synthesize B-cell lymphoma (Bcl-3), a protein that regulates clot retraction in murine and human platelets. We show that α-toxin induced αIIbβ3-dependent aggregation (EC50 2.98 µg/mL ± 0.64 µg/mL) and, over time, significantly altered platelet morphology and stimulated de novo accumulation of Bcl-3 protein in platelets. Adherence to collagen or fibrinogen also increased the expression of Bcl-3 protein by platelets. α-toxin altered Bcl-3 protein expression patterns in platelets adherent to collagen, but not fibrinogen. Pretreatment of platelets with inhibitors of protein synthesis or the mammalian Target of Rapamycin (mTOR) decreased Bcl-3 protein expression in α-toxin stimulated platelets. In conclusion, Staphylococcus aureus-derived α-toxin, a pore forming exotoxin, exerts immediate (i.e., aggregation) and prolonged (i.e., protein synthesis) responses in platelets, which may contribute to increased thrombotic events associated with gram-positive sepsis or endocarditis

Rituximab, gemcitabine and oxaliplatin in relapsed or refractory indolent and mantle cell lymphoma: results of a multicenter phase I/II-study of the German Low Grade Lymphoma Study Group

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005

Real-life data on treatment and outcomes in advanced ovarian cancer : An observational, multinational cohort study (RESPONSE trial)

Background This study aimed to describe the treatment strategies and outcomes for women with newly diagnosed advanced high-grade serous or endometrioid ovarian cancer (OC). Methods This observational study collected real-world medical record data from eight Western countries on the diagnostic workup, clinical outcomes, and treatment of adult women with newly diagnosed advanced (Stage III-IV) high-grade serous or endometrioid OC. Patients were selected backward in time from April 1, 2018 (the index date), with a target of 120 patients set per country, followed for >= 20 months. Results Of the 1119 women included, 66.9% had Stage III disease, 11.7% had a deleterious BRCA mutation, and 26.6% received bevacizumab; 40.8% and 39.3% underwent primary debulking surgery (PDS) and interval debulking surgery (IDS), respectively. Of the patients who underwent PDS, 55.5% had no visible residual disease (VRD); 63.9% of the IDS patients had no VRD. According to physician-assessed responses (at the first assessment after diagnosis and treatment), 53.2% of the total population had a complete response and 25.7% had a partial response to first-line chemotherapy after surgery. After >= 20 months of follow-up, 32.9% of the patients were disease-free, 46.4% had progressive disease, and 20.6% had died. Bevacizumab use had a significant positive effect on overall survival (hazard ratio [HR], 0.62; 95% CI, 0.42-0.91; p = .01). A deleterious BRCA status had a significant positive effect on progression-free survival (HR, 0.60; 95% CI, 0.41-0.84; p < .01). Conclusions Women with advanced high-grade serous or endometrioid OC have a poor prognosis. Bevacizumab use and a deleterious BRCA status were found to improve survival in this real-world population. Lay summary Patients with advanced (Stage III or IV) ovarian cancer (OC) have a poor prognosis. The standard treatment options of surgery and chemotherapy extend life beyond diagnosis for 5 years or more in only approximately 45% of patients. This study was aimed at describing the standard of care in eight Western countries and estimating how many patients who are diagnosed with high-grade serous or endometrioid OC could potentially be eligible for first-line poly(adenosine diphosphate ribose) polymerase inhibitor (PARPi) maintenance therapy. The results highlight the poor prognosis for these patients and suggest that a significant proportion (79%) would potentially be eligible for first-line PARPi maintenance treatment.Peer reviewe

Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61–65 years (S2, n = 107) and 66–70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray’s p = 0.83) and non-relapse mortality (Gray’s p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age