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The initiation of CD8+ T cell responses against dead cell–associated Ags is tightly regulated, facilitating adaptive immunity against pathogens and tumors while preventing autoimmunity. It is now well established that dying cells actively regulate the generation of CD8+ T cell responses via the release or exposure of damage-associated molecular patterns. However, it is unclear whether nonproteasomal proteases (activated in stressed and dying cells) can influence the availability of Ags for cross-presentation. Using a mouse model of immunogenic necrosis, we investigated the role of tumor-derived proteases in the priming of CD8+ T cells. We demonstrate that proteases released from necrotic tumor cells can degrade whole-protein Ag, generating proteolytic intermediates that are efficiently cross-presented by dendritic cells and enhance CD8+ T cell cross-priming. We identify a dominant role for calpain proteases, which are activated during necrotic cell death induced by severe heat shock. Mechanistically, proteolytic intermediates generated by tumor-derived proteases associate with necrotic tumor cell debris, which acts as a vehicle for Ag transfer that facilitates highly efficient cross-presentation in dendritic cells. Our results suggest that proteolytic systems activated in Ag donor cells during cell death may influence the availability of antigenic substrates for cross-presentation, thereby regulating the antigenicity of cell death.

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions.

Hematologic and oncologic patients with chemo- or immunotherapy-related immunosuppression are at substantial risk for bacterial infections and Pneumocystis jirovecii pneumonia (PcP). As bacterial resistances are increasing worldwide and new research reshapes our understanding of the interactions between the human host and bacterial commensals, administration of antibacterial prophylaxis has become a matter of discussion. This guideline constitutes an update of the 2013 published guideline of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO). It gives an overview about current strategies for antibacterial prophylaxis in cancer patients while taking into account the impact of antibacterial prophylaxis on the human microbiome and resistance development. Current literature published from January 2012 to August 2020 was searched and evidence-based recommendations were developed by an expert panel. All recommendations were discussed and approved in a consensus conference of the AGIHO prior to publication. As a result, we present a comprehensive update and extension of our guideline for antibacterial and PcP prophylaxis in cancer patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-021-04452-9.

OBJECTIVE To consider the effects of whole-grain processing, specifically milling, on glycemic control in free-living adults with type 2 diabetes. RESEARCH DESIGN AND METHODS Participants of this crossover trial were randomized to two interventions of 2 weeks, separated by washout. They were advised to replace the grain foods they normally consumed with intervention foods. Intervention foods were nutrient-matched whole-grain products of wheat, oats, and brown rice that differed in their degree of processing. No other lifestyle advice was given. Continuous glucose monitoring systems were worn. Other cardiometabolic risk factors and alkylresorcinols (a biomarker of whole-grain intake) were measured pre- and postintervention. RESULTS Thirty-one adults with type 2 diabetes (63 ± 13 years old, BMI 32.4 ± 7 kg/m2, HbA1c 7.5 ± 3.4% [59 ± 14 mmol/mol]) commenced the trial; 28 (90%) completed both interventions. The increase in alkylresorcinols did not differ between interventions, and there was no difference in reported energy intake. Postprandial responses were 9% (95% CI 3–15) lower following breakfast and 6% (1–10) lower following all meals of less-processed whole grains when compared with finely milled grains. Day-long glycemic variability also was reduced when measured by 24-h SD (−0.16 mmol/L [95% CI −0.25 to −0.06]) and mean amplitude of glycemic excursion (−0.36 [95% CI −0.65 to −0.08]). Mean change in body weight differed by 0.81 kg (95% CI 0.62–1.05) between interventions, increasing during the finely milled intervention and decreasing during the less-processed whole-grain intervention. This was not a mediating factor for the glycemic variables considered. CONCLUSIONS Consuming less-processed whole-grain foods over 2 weeks improved measures of glycemia in free-living adults with type 2 diabetes compared with an equivalent amount of whole-grain foods that were finely milled. Dietary advice should promote the consumption of minimally processed whole grains.

The initiation of CD8

Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial&ndash, mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy.

Objective: To consider the effects of wholegrain processing, specifically milling, on glycaemic control in free-living adults with type 2 diabetes. Research Design and Methods: Participants of this crossover trial were randomised to two interventions of two-weeks, separated by washout. They were advised to replace the grain foods they normally consumed with intervention foods. Intervention foods were nutrient matched wholegrain products of wheat, oats, and brown rice that differed in their degree of processing. No other lifestyle advice was given. Continuous glucose monitoring systems were worn. Other cardiometabolic risk factors and alkylresorcinols (a biomarker of wholegrain intake) were measured pre and post interventions. Results: 31 adults with type 2 diabetes (63±13 years old, BMI 32.4±7, HbA1c 7.5±3.4% (59±14mmol/mol)) commenced the trial, 28 (90%) completed both interventions. The increase in alkylresorcinols did not differ between interventions and there was no difference in reported energy intake. Postprandial responses were 9% (95%CI 3-15%) lower following breakfast and 6% (95%CI 1-10%) lower following all meals of less processed whole grains when compared with finely milled grains. Day-long glycaemic variability also reduced when measured by 24-hour standard deviation (-0.16mmol/l 95%CI -0.25 to -0.06) and MAGE (-0.36 95%CI -0.65 to -0.08). Mean change in body weight differed by 0.81kg (95%CI 0.62 to 1.05) between interventions, increasing during the finely milled intervention and decreasing during the less processed wholegrain intervention. This was not a mediating factor for the glycaemic variables considered. Conclusions: Consuming less processed wholegrain foods over two weeks improved measures of glycaemia in free-living adults with type 2 diabetes when compared with an equivalent amount of wholegrain foods that were finely milled. Dietary advice should promote the consumption of minimally processed whole grains.

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy.

Im Jahr 2008 grundet Silke Neumann die Agentur fur Kulturkommunikation Bureau N. Die Zeit fur eine Unternehmensgrundung ist gunstig. Der Berliner Kunstmarkt befindet sich im Umbruch. Kunst, Kultur und Kreativitat gehoren zu den Wachstumsmotoren der Berliner Wirtschaft und werden zu Markenzeichen der Stadt (Senatsverwaltung fur Wirtschaft, Energie und Betriebe 2014). Kunstler, Galerien und Kulturschaffende zieht es nach Berlin, sie suchen nach Vernetzung und Profilierung. Beides kann Bureau N anbieten. Mit zunehmender Bekanntheit wachst das Unternehmen auch in andere Aufgaben und Geschaftsfelder hinein und entwickelt heute Kommunikationskonzepte und Markenstrategien fur die Kreativwirtschaft.

Background and Purpose— Human amnion epithelial cells (hAECs) are nonimmunogenic, nontumorigenic, anti-inflammatory cells normally discarded with placental tissue. We reasoned that their profile of biological features, wide availability, and the lack of ethical barriers to their use could make these cells useful as a therapy in ischemic stroke. Methods— We tested the efficacy of acute (1.5 hours) or delayed (1–3 days) poststroke intravenous injection of hAECs in 4 established animal models of cerebral ischemia. Animals included young (7–14 weeks) and aged mice (20–22 months) of both sexes, as well as adult marmosets of either sex. Results— We found that hAECs administered 1.5 hours after stroke in mice migrated to the ischemic brain via a CXC chemokine receptor type 4-dependent mechanism and reduced brain inflammation, infarct development, and functional deficits. Furthermore, if hAECs administration was delayed until 1 or 3 days poststroke, long-term functional recovery was still augmented in young and aged mice of both sexes. We also showed proof-of-principle evidence in marmosets that acute intravenous injection of hAECs prevented infarct development from day 1 to day 10 after stroke. Conclusions— Systemic poststroke administration of hAECs elicits marked neuroprotection and facilitates mechanisms of repair and recovery.

Raman spectroscopy (RS) has been used as a powerful diagnostic and non-invasive tool in cancer diagnosis as well as in discrimination of cancer and immune cells. In this study RS in combination with chemometrics was applied to cellular Raman spectral data to distinguish the phenotype of T-cells and monocytes after incubation with media conditioned by glioblastoma stem-cells (GSCs) showing different molecular background. For this purpose, genetic modulations of epithelial-to-mesenchymal transition (EMT) process and expression of immunomodulator CD73 were introduced. Principal component analysis of the Raman spectral data showed that T-cells and monocytes incubated with tumour-conditioned media (TCMs) of GSCs with inhibited EMT activator ZEB1 or CD73 formed distinct clusters compared to controls highlighting their differences. Further discriminatory analysis performed using linear discriminant analysis (LDA) and support vector machine classification (SVM), yielded sensitivities and specificities of over 70 and 67% respectively upon validation against an independent test set. Supporting those results, flow cytometric analysis was performed to test the influence of TCMs on cytokine profile of T-cells and monocytes. We found that ZEB1 and CD73 influence T-cell and monocyte phenotype and promote monocyte differentiation into a population of mixed pro- and anti-tumorigenic macrophages (MΦs) and dendritic cells (DCs) respectively. In conclusion, Raman spectroscopy in combination with chemometrics enabled tracking T-cells and monocytes.

Successful bacterial pathogens produce an array of virulence factors that allow subversion of the immune system and persistence within the host. For example, uropathogenic Escherichia coli strains, such as CFT073, express Toll/IL-1 receptor-containing (TIR-containing) protein C (TcpC), which impairs TLR signaling, thereby suppressing innate immunity in the urinary tract and enhancing persistence in the kidneys. Here, we have reported that TcpC also reduces secretion of IL-1β by directly interacting with the NACHT leucin-rich repeat PYD protein 3 (NLRP3) inflammasome, which is crucial for recognition of pathogens within the cytosol. At a low MOI, IL-1β secretion was minimal in CFT073-infected macrophages; however, IL-1β release was markedly increased in macrophages infected with CFT073 lacking tcpC. Induction of IL-1β secretion by CFT073 and tcpC-deficient CFT073 required the NLRP3 inflammasome. TcpC attenuated activation of the NLRP3 inflammasome by binding both NLRP3 and caspase-1 and thereby preventing processing and activation of caspase-1. Moreover, in a murine urinary tract infection model, CFT073 infection rapidly induced expression of the NLRP3 inflammasome in the bladder mucosa; however, the presence of TcpC in WT CFT073 reduced IL-1β levels in the urine of infected mice. Together, these findings illustrate how uropathogenic E. coli use the multifunctional virulence factor TcpC to attenuate innate immune responses in the urinary tract.

Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells.

Tonic inhibitory currents, mediated by extrasynaptic GABAA receptors, are elevated at a delay following stroke. Flavonoids minimise the extent of cellular damage following stroke, but little is known about their mode of action. We demonstrate that the flavonoid, 2′-methoxy-6-methylflavone (0.1–10 µM; 2′MeO6MF), increases GABAA receptor tonic currents presumably via δ-containing GABAA receptors. Treatment with 2′MeO6MF 1–6 h post focal ischaemia dose dependently decreases infarct volume and improves functional recovery. The effect of 2′MeO6MF was attenuated in δ−/− mice, indicating that the effects of the flavonoid were mediated via δ-containing GABAA receptors. Further, as flavonoids have been shown to have multiple modes of action, we investigated the anti-inflammatory effects of 2′MeO6MF. Using a macrophage cell line, we show that 2′MeO6MF can dampen an LPS-induced elevation in NFkB activity. Assessment of vehicle-treated stroke animals revealed a significant increase in circulating IL1β, TNFα and IFγ levels. Treatment with 2′MeO6MF dampened the stroke-induced increase in circulating cytokines, which was blocked in the presence of the pan-AKT inhibitor, GSK690693. These studies support the hypothesis that compounds that potentiate tonic inhibition via δ-containing GABAA receptors soon after stroke can afford neuroprotection.

[EN] Background: As people become older, the biological process of aging leads to a decline in functional capabilities, which entails difficulties in the performance of daily tasks. Within the "Active and Assisted Living Joint Programme" a consortium from Spain, Germany, and Switzerland developed an interactive Exergame software for older adults to maintain their physical abilities and independence within the daily tasks. Subjects and Methods: An interventional study was conducted to validate the software. For 3 months, Swiss and Spanish seniors used the system at least three times a week for minimum half an hour in their homes. The physical condition in terms of maintaining or increasing strength, balance, safety, and mobility of the seniors was assessed by using the Berg Balance Scale and the Senior Fitness Test. In addition, the effect on independence within the activities of daily living was assessed by using the Canadian Occupational Performance Measure, the Performance Quality Rating Scale, and the Iconographical Falls Efficacy Scale. We used the EQ 5D to evaluate the "quality of life." Results: Twenty-nine participants (male; n= 14; female; n= 15) completed the study. Scores of endurance (2 minutes step test; P=0.01, eta(2) = 0.3) increased significantly. Moderate effect sizes in quality of life (r= 0.3), lower body strength (eta(2)= 0.08), and large effect sizes in endurance (eta(2) = 0.3) were detected. A small effect was evaluated within the gait speed (r= 0.2), mobility in the lower body (r= 0.2), and the balance capabilities (r= 0.2). Conclusion: The results of this study lead us to the conclusion that physical training with activity-focused exergames that are related to the everyday tasks of older adults could help to maintain and improve the individual fitness status., This project was funded by the AAL Joint Programme: Call AAL-2012-5, ICT-based solutions for supporting occupation in life of older adults and the Swiss Confederation, Federal Department of Economic Affairs, Education and Research. We thank all our partners of the consortium as well as all seniors who participated in the project.

The lipid antigen α-galactosylceramide (α-GalCer) is a potent activator of invariant natural killer T-cells (iNKT cells) and can stimulate cytotoxic and anti-tumour immune responses. However optimal responses appear to be induced by α-GalCer when cell-based vaccines are delivered intravenously. Here we investigated if co-delivery of protein and peptide antigens along with α-GalCer in a liposomal formulation could stimulate therapeutic anti-tumour immune responses. Cationic liposomes were inherently immune-stimulatory and induced cytotoxic immune responses when delivered both by intravenous and subcutaneous injection. However, only vaccine delivered intravenously stimulated therapeutic anti-tumour immune responses to a peptide antigen. Surface modification with polyethylene glycol (PEG) did not improve immune responses to either intravenously or subcutaneously delivered vaccines. Immune responses to short and long peptide sequences (CD8 and CD4 epitopes) of the self-antigen tyrosinase-related protein 2 (TRP2) as a vaccine antigen, co-delivered with α-GalCer in either cationic liposomes or PBS were further examined. Enhanced production of IFN-γ, increased cytotoxic T-cell responses and tumour survival were observed when a long TRP2-peptide was delivered with α-GalCer in cationic liposomes.

Reactivation of viral infections is common in patients with solid tumour or haematological malignancy. Incidence and severity depend on the extent of cellular immunosuppression. Antiviral prophylaxis may be effective to prevent viral reactivation. In 2006, the Infectious Diseases Working Party of German Society for Hematology and Medical Oncology (DGHO) published guidelines for antiviral prophylaxis in these patient populations. Here, we present an update of these guidelines for patients with solid and haematological malignancies undergoing antineoplastic treatment but not allogeneic stem cell transplantation. Relevant literature for reactivation of different viruses (herpes simplex virus (HSV), varicella zoster virus (VZV), hepatitis B virus (HBV) and respiratory viruses) is discussed to provide evidence-based recommendations for clinicians taking care of this patient population. We recommend a risk-adapted approach with (val)acyclovir against HSV and VZV in patients treated with alemtuzumab, bortezomib or purine analogues. Seasonal vaccination against influenza is recommended for all patients with solid or haematological malignancies regardless of antineoplastic therapy. Hepatitis B screening is recommended in lymphoproliferative disorders, acute leukaemia, and breast cancer, and during treatment with monoclonal anti-B-cell antibodies, anthracyclines, steroids and in autologous stem cell transplantation. In those with a history of hepatitis B prophylactic lamivudine, entecavir or nucleotide analogues as adefovir are recommended to prevent reactivation.

The bacterial strategy of chemotaxis relies on temporal comparisons of chemical concentrations, where the probability of maintaining the current direction of swimming is modulated by changes in stimulation experienced during the recent past. A short-term memory required for such comparisons is provided by the adaptation system, which operates through the activity-dependent methylation of chemotaxis receptors. Previous theoretical studies have suggested that efficient navigation in gradients requires a well-defined adaptation rate, because the memory time scale needs to match the duration of straight runs made by bacteria. Here we demonstrate that the chemotaxis pathway of Escherichia coli does indeed exhibit a universal relation between the response magnitude and adaptation time which does not depend on the type of chemical ligand. Our results suggest that this alignment of adaptation rates for different ligands is achieved through cooperative interactions among chemoreceptors rather than through fine-tuning of methylation rates for individual receptors. This observation illustrates a yet-unrecognized function of receptor clustering in bacterial chemotaxis.

Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII).

Particulate vaccine formulations, designed to improve the delivery of antigens to antigen-presenting cells (APCs) and to stimulate an immune response, have been shown to activate the NLRP3 inflammasome. This leads to the processing and secretion of interleukin (IL)-1β, which supports the recruitment of pro-inflammatory immune cells into the tissue and can therefore be beneficial for vaccine potency. Recent work suggested that this may be a common mechanism of action for all particulate formulations. The aim of this study was to investigate whether the activation of the NLRP3 inflammasome was common to many delivery systems. We prepared polymer-based chitosan nanoparticles (CNPs), lipid-based cubosomes, a water in oil emulsion of incomplete Freund's adjuvant (IFA) and alum formulations and examined inflammasome activation in vitro using murine bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells and in vivo in mice. The formulations differed in their morphology, size and zeta-potential. Only the positively charged particles (CNPs and alum) were able to activate the inflammasome and increase the secretion of IL-1β. A decrease in the activation of the inflammasome with these particulates was observed when cathepsin B-mediated effects were blocked, implying a role of lysosomal rupture in the activation process. These findings demonstrate a role for the surface charge of particulates in the activation of the NLRP3 inflammasome, which should be considered when designing a novel vaccine formulation.

Meropenem is an effective β-lactam antibiotic that is frequently used to treat serious infections in both intensive care unit (ICU) and febrile neutropenic hematology/oncology (Hem/Onc) patients. Studies suggest that to be effective, meropenem concentrations must be maintained above the inhibitory concentrations for the majority of a dosing interval. However, the pharmacokinetics (PK) of meropenem seem to differ in critically ill patients compared with healthy or less ill subjects used to select labeled dosing regimens.This study was designed to investigate meropenem PK in critically ill patients and to see how often standard dosing regimens produced adequate plasma concentrations. A secondary objective was to investigate how achieved concentrations were related to outcomes (morbidity and mortality) in these patients.Meropenem plasma concentrations over time were measured using a high pressure liquid chromatography assay in febrile Hem/Onc and ICU patients who were treated with standard meropenem dosing schedules. Outcomes such as fever control and survival were assessed in these patients and compared with individual meropenem PK data and with recommended target concentrations.A total of 25 subjects including 10 febrile Hem/Onc and 15 ICU patients with a variety of serious illnesses and baseline renal function were studied. Mean peak concentrations were less variable than were pre-dose concentrations. Post peak and trough concentrations were often below recommended minimum inhibitory concentrations. Both clearance and volumes of distribution were greater than reported in less ill subjects, only in part explained by increased renal clearance. Therefore, serum concentrations often did not exceed recommended concentration targets even for moderately sensitive organisms. Inadequate concentrations were especially common in the mostly ill, febrile neutropenic Hem/Onc subjects and seemed to explain at least some therapeutic failures. Conversely, drug accumulation occurred in ICU subjects with decreased renal function.Standard meropenem dosing regimens were inadequate in many critically ill febrile, neutropenic Hem/Onc, and septic ICU patients. These data suggest a role for meropenem concentration monitoring in such patients.

Most professional translators in the Western world are heavy computer users and thus may be exposed to health risks known to be associated with computer work. These include musculoskeletal ailments of the upper extremities, back, shoulders, arms, hands and problems with the eyes. This paper reports on the findings of workplace assessments and interviews with professional translators with respect to the ergonomics of their workplaces and related health issues. A total of 36 professional translators working as freelancers, in institutional settings or in commercial enterprises were visited at their workplaces. Each workplace was assessed and compared to the recommendations about ergonomics available in the literature. In addition, interviews were held with translators immediately after the assessments about their current health status and any recent complaints. Many of the assessed workplaces evinced a high standard of ergonomically appropriate equipment and furniture. However, the equipment was in many cases not adjusted to suit the ergonomic needs of the individual using the workplace. Although the level of complaints was low overall, the highest number of health complaints related to the eyes, neck and shoulder girdle. Frequent breaks, changing position and doing short exercises to loosen up tense muscles would address these problems by helping to reduce tension and pain in the neck, shoulders and back and by providing rest for the eyes. Whenever possible, an ergonomic consultation is recommended. It is also recommended that ergonomic knowledge about proper workplace set-up should be provided in professional training. La plupart des traducteurs professionnels occidentaux restent assis de longues heures devant leur écran et s’exposent ainsi aux problèmes de santé liés au travail à l’ordinateur. Parmi ces problèmes, il convient de citer les troubles musculo-squelettiques du dos, des épaules, des bras et des mains et la fatigue oculaire. Le présent article expose les résultats des évaluations et interviews réalisées auprès de traducteurs professionnels et axées sur l’ergonomie de leur poste de travail et les problèmes de santé associés. Les chercheurs se sont rendus aux postes de travail de 36 traducteurs professionnels installés à leur compte ou engagés dans des institutions ou des entreprises commerciales. Chaque poste de travail a fait l’objet d’une évaluation et d’une comparaison avec les recommandations en matière d’ergonomie fournies par la littérature. Des interviews ont, en outre, été menées avec les traducteurs à l’issue des évaluations dans le but de connaître leur état de santé et d’éventuels problèmes récents. Une grande partie des postes évalués présentent un équipement et un mobilier dotés d’un niveau élevé d’ergonomie. Toutefois, l’agencement n’est pas toujours adapté aux besoins ergonomiques de la personne assignée au poste de travail. Même si, dans l’ensemble, le nombre de problèmes de santé exprimés reste faible, la majorité d’entre eux concernent les yeux, la nuque et la ceinture scapulaire. Pauses fréquentes, changements de position et brefs exercices de relaxation permettraient de soulager ces problèmes en apaisant les tensions et les douleurs au niveau du dos, des épaules et de la nuque et en reposant les yeux. Il est recommandé de procéder à une analyse ergonomique dans la mesure du possible et de sensibiliser l’auditoire à l’agencement adéquat du poste de travail dans le cadre de formations professionnelles.

Despite the fact that professional translation is characterized by human-machine interaction, the ergonomics of the professional translation workplace is relatively under-researched. In order to gain further insights into how translators worldwide have set up and organized their workplaces, an anonymous online survey was developed by a team of researchers in translation studies and occupational therapy as part of an interdisciplinary project. It was made available in six languages (English, French, German, Italian, Portuguese, and Spanish) and distributed through multipliers such as professional organizations. The interest that this topic generated in the professional community was reflected not only in the large number of completed questionnaires (1,850) but also by the comments provided by translators both in the survey itself and in email messages to the research team. This paper reports on the findings of the survey with a focus on differences existing among commercial, institutional, and freelance translators in different countries and the degree to which language technology is involved in professional translation. Findings are compared to good practice recommendations for computer work, and conclusions are drawn with respect to health issues related to suboptimal ergonomics. Alors même que la traduction professionnelle se caractérise par une interaction entre l’humain et la machine, l’ergonomie chez les traductrices et traducteurs professionnels reste un domaine relativement peu exploré. Dans le but de recueillir des informations sur la façon dont les traductrices et traducteurs à travers le monde ont agencé et organisé leur poste de travail, des chercheuses en traductologie et en ergothérapie ont réalisé une étude en ligne anonyme dans le cadre d’un projet interdisciplinaire. Traduit en six langues (français, anglais, allemand, italien, portugais et espagnol), le questionnaire relatif à cette étude fut envoyé par des multiplicateurs, par exemple des organisations professionnelles. L’intérêt suscité par la question au sein de la communauté professionnelle se reflète dans le grand nombre de questionnaires complétés (1 850), mais aussi dans les commentaires formulés par les traducteurs dans l’étude elle-même et dans les courriels adressés à l’équipe de chercheuses. Le présent article expose les résultats de l’étude et met l’accent sur les disparités entre traducteurs commerciaux, institutionnels et indépendants dans les différents pays et sur le degré de pénétration de la technologie langagière dans la traduction professionnelle. Les résultats font l’objet d’une comparaison avec les recommandations en matière de bonnes pratiques dans le travail à l’ordinateur et servent de base à l’analyse des problèmes de santé liés à une ergonomie insuffisante.

Annals of hematology 95(9), 1435-1455 (2016). doi:10.1007/s00277-016-2711-1, Published by Springer, Berlin

Die Slackline ist ein Trainingsgerat, mit dem uberwiegend Kletterer und Boulderer ihre Gleichgewichtsfahigkeit schulen. Ihren Ursprung hat die Slackline 1980 in den USA, als Kletterbegeisterte im Yosemite Nationalpark anstatt auf einer starren Absperrkette eines Parkplatzes auf einem Nylonband, das sie zwischen zwei Baumen spannten, balancierten. Mittlerweile trainieren damit nicht nur Kletterer, sondern auch im Sportunterricht und als Freizeitbeschaftigung gewinnt die Slackline immer mehr an Bedeutung. Silke Neumann und Roger Stadelmann zeigen, wie sie die Slackline als Therapiegerat in der neurologischen Rehabilitation einsetzen, und komplettieren ihren Artikel durch drei Erfahrungsberichte von Patienten, die eine Slackline-Therapie erfolgreich hinter sich gebracht haben.

Background Neutropenic patients are at risk of abdominal complications and yet the incidence and impact of these complications on patients’ morbidity and mortality have not been sufficiently evaluated. We aimed to assess a clinical rule for early detection of abdominal complications leading to death or transfer to intensive care in patients with chemotherapy-associated neutropenia. Design and Methods This observational multicenter study was carried out in seven German hematology-oncology departments. For inclusion, neutropenia of at least 5 consecutive days was required. Risk factors for “transfer to intensive care” and “death” were assessed by backward-stepwise binary logistic regression analyses. Chemotherapy-associated bowel syndrome was defined as a combination of fever (T ≥37.8 °C) and abdominal pain and/or lack of bowel movement for 72 hours or more. Five hundred and twenty-one neutropenic episodes were documented in 359 patients. Results The incidence of chemotherapy-associated bowel syndrome was 126/359 (35%) in first episodes of neutropenia. Transfer to intensive care occurred in 41/359 (11%) and death occurred in 17/359 (5%) first episodes. Chemotherapy-associated bowel syndrome and duration of neutropenia were identified as risk factors for transfer to intensive care ( P

In user-centred design and marketing, personas are fictional characters created to represent the different user types that might use a site, brand, or product in a similar way [1]. As in other projects, the main application and use value of the persona approach in WeTakeCare project has been to depict and thus make "vivid" the characters and the milieus created and selected. It has helped to better understand and communicate the differences among the potential users. It has also helped to understand the heterogeneity and diversity of the users' lives and to focus on how to meet their actual needs [2].