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Schaible A.M.,Friedrich - Schiller University of Jena | Koeberle A.,Friedrich - Schiller University of Jena | Northoff H.,University Medical Center Tuebingen | Lawrenz B.,University Hospital of Tuebingen | And 4 more authors.
Prostaglandins Leukotrienes and Essential Fatty Acids | Year: 2013

Pregnancy is accompanied by major immunological changes to maintain both tolerance for the fetus and immune competence. Leukotrienes are powerful 5-lipoxygenase-derived inflammatory mediators and the characteristics of leukotriene-related diseases (e.g., asthma, allergic rhinitis) change during pregnancy. Here, we show that pregnancy affects leukotriene synthesis in human blood and leukocytes. 5-Lipoxygenase product formation in stimulated blood of pregnant women was significantly higher than in non-pregnant females. Although a pregnancy-related increase in neutrophil and monocyte counts may explain these observations, granulocytes of pregnant donors have lower leukotriene-synthetic capacities. On the other hand, granulocytes from non-pregnant woman produced more leukotrienes when resuspended in plasma of pregnant women than of non-pregnant females. Together, we show that leukotriene biosynthesis in maternal blood is increased by the interrelations of higher leukocyte numbers, lower cellular capacity for leukotriene synthesis and stimulatory effects of plasma. This bias may affect leukotriene-related diseases during pregnancy and their pharmacological treatment. © 2013 Elsevier Ltd.


Pergola C.,Friedrich - Schiller University of Jena | Schaible A.M.,Friedrich - Schiller University of Jena | Nikels F.,Friedrich - Schiller University of Jena | Dodt G.,University of Tübingen | And 2 more authors.
Pharmacological Research | Year: 2015

5-Lipoxygenase (5-LO), the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) from arachidonic acid, is regulated by androgens in human neutrophils and monocytes accounting for sex differences in LT formation. Here we show that progesterone suppresses the synthesis of 5-LO metabolites in human primary monocytes. 5-LO product formation in monocytes stimulated with Ca2+-ionophore A23187 or with lipopolysaccharide/formyl peptide was suppressed by progesterone at concentrations of 10-100 nM in cells from females and at 1 μM in cells from males. Progesterone down-regulated 5-LO product formation in a rapid and reversible manner, but did not significantly inhibit 5-LO activity in cell-free assays using monocyte homogenates. Also, arachidonic acid release and its metabolism to other eicosanoids in monocytes were not significantly reduced by progesterone. The inhibitory effect of progesterone on LTs was still observed when mitogen-activated protein kinases were pharmacologically blocked, stimulatory 1-oleoyl-2-acetyl-sn-glycerol was exogenously supplied, or extracellular Ca2+ was removed by chelation. Instead, suppression of PKA by means of two different pharmacological approaches (i.e. H89 and a cell-permeable PKA inhibitor peptide) prevented inhibition of 5-LO product generation by progesterone, to a similar extent as observed for the PKA activators prostaglandin E2 and 8-Br-cAMP, suggesting the involvement of PKA. In summary, progesterone affects the capacity of human primary monocytes to generate 5-LO products and, in addition to androgens, may account for sex-specific effects on pro-inflammatory LTs. © 2015 Elsevier Ltd. All rights reserved.


Maier S.,Albert Ludwigs University of Freiburg | Szalkowski A.,Albert Ludwigs University of Freiburg | Kamphausen S.,Albert Ludwigs University of Freiburg | Kamphausen S.,University Medical Center Tuebingen | And 8 more authors.
PLoS ONE | Year: 2012

Recent studies have begun to carve out a specific role for the rostral part of the dorsal medial prefrontal cortex (dmPFC) and adjacent dorsal anterior cingulate cortex (dACC) in fear/anxiety. Within a novel general framework of dorsal mPFC/ACC areas subserving the appraisal of threat and concomitant expression of fear responses and ventral mPFC/ACC areas subserving fear regulation, the rostral dmPFC/dACC has been proposed to specifically mediate the conscious, negative appraisal of threat situations including, as an extreme variant, catastrophizing. An alternative explanation that has not been conclusively ruled out yet is that the area is involved in fear learning. We tested two different fear expression paradigms in separate fMRI studies (study 1: instructed fear, study 2: testing of Pavlovian conditioned fear) with independent groups of healthy adult subjects. In both paradigms the absence of reinforcement precluded conditioning. We demonstrate significant BOLD activation of an identical rostral dmPFC/dACC area. In the Pavlovian paradigm (study 2), the area only activated robustly once prior conditioning had finished. Thus, our data argue against a role of the area in fear learning. We further replicate a repeated observation of a dissociation between peripheral-physiological fear responding and rostral dmPFC/dACC activation, strongly suggesting the area does not directly generate fear responses but rather contributes to appraisal processes. Although we succeeded in preventing extinction of conditioned responding in either paradigm, the data do not allow us to definitively exclude an involvement of the area in fear extinction learning. We discuss the broader implications of this finding for our understanding of mPFC/ACC function in fear and in negative emotion more generally. © 2012 Maier et al.


Jors K.,Albert Ludwigs University of Freiburg | Adami S.,Albert Ludwigs University of Freiburg | Xander C.,Albert Ludwigs University of Freiburg | Meffert C.,Albert Ludwigs University of Freiburg | And 6 more authors.
Cancer | Year: 2014

METHODS: In this cross-sectional study, the authors surveyed physicians and nurses in 16 hospitals belonging to 10 cancer centers in Baden-Wuerttemberg, Germany. A revised questionnaire from a previous study was used, addressing the following topics regarding end-of-life care: structural conditions (ie, rooms, staff), education/training, working environment, family/caregivers, medical treatment, communication with patients, and dignified death.RESULTS: In total, 1131 surveys (response rate 5 50%) were returned. Half of the participants indicated that they rarely have enough time to care for dying patients, and 55% found the rooms available for dying patients unsatisfactory. Only 19% of respondents felt that they had been well-prepared to care for the dying (physicians 5 6%). Palliative care staff reported much better conditions for the dying than staff from other wards (95% of palliative care staff indicated that patients die in dignity on their ward). Generally, physicians perceived the circumstances much more positively than nurses, especially regarding communication and lifeprolonging measures. Overall, 57% of respondents believed that patients could die with dignity on their ward.BACKGROUND: Prior research has shown that hospitals are often ill-prepared to provide care for dying patients. This study assessed whether the circumstances for dying on cancer center wards allow for a dignified death.CONCLUSIONS: Only about half of the respondents perceived that a dignified death is possible on their ward. We recommend that cancer centers invest more in staffing, adequate rooms for dying patients, training in end-of-life care, advance-care planning standards, and the early integration of specialist palliative care services. © 2014 American Cancer Society.


Pergola C.,Friedrich - Schiller University of Jena | Jazzar B.,University of Tübingen | Rossi A.,University of Naples Federico II | Buehring U.,University of Tübingen | And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Lipoxygenases (LOs) are iron-containing enzymes that catalyze the conversion of arachidonic acid into hydroperoxyeicosatetraenoic acids (HPETEs) and other bioactive lipid mediators. In mammals, 5-LO, 15-LO, and 12-LO enzymes seem to have distinct roles in pathophysiological contexts, which have emphasized the need for selective inhibitors. Cinnamyl-3,4-dihydroxy-α- cyanocinnamate (CDC) has been proposed as potent and selective inhibitor of platelet-type 12-LO (p12-LO). Here, we re-evaluated the selectivity profile of CDC on LOs, and we show that CDC is a potent and direct inhibitor of 5-LO. CDC reduced 5-LO activity in cell-free assays (purified human recombinant enzyme or leukocyte homogenates), with IC50 values in the low nanomolar range (9-25 nM) and a selectivity index of approximately 35 and 15 over p12-LO and 15-LO1, respectively. Likewise, CDC inhibited 5-LO product formation in intact human polymorphonuclear leukocytes and monocytes (IC50 = 0.45-0.8 μM). A lower potency was observed for 15-LO1, whereas p12-LO activity in platelets was hardly affected. In human whole blood, CDC efficiently reduced the formation of 5-LO products, and similar effects were observed for 12(S)-H(P)ETE and 15(S)-H(P)ETE. Finally, CDC (3.5 and 7 mg/kg i.p.) was effective in vivo in the platelet-activating factor-induced shock in mice and reduced formation of the 5-LO product leukotriene B4 in the rat carrageenan-induced pleurisy after a single oral dose of 10 mg/kg. Together, our data demonstrate that CDC is a potent inhibitor of 5-LO with efficacy in vivo and encourage further development of CDC as the lead compound. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.


Maier S.J.,Albert Ludwigs University of Freiburg | Szalkowski A.,Albert Ludwigs University of Freiburg | Kamphausen S.,University Medical Center Tuebingen | Feige B.,Albert Ludwigs University of Freiburg | And 7 more authors.
Psychological Medicine | Year: 2014

Background Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). Method In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS-were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS-during testing. No UCS was presented. Results Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. Conclusions During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS-related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD. © 2013 Cambridge University Press.


Stoleriu M.G.,University Medical Center Tuebingen | Steger V.,University Medical Center Tuebingen | Mustafi M.,University Medical Center Tuebingen | Michaelis M.,University of Canterbury | And 6 more authors.
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery | Year: 2014

OBJECTIVES: According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)].METHODS: Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37°C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37°C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection.RESULTS: The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group.CONCLUSIONS: In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy. © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.


PubMed | University Medical Center Tuebingen, University of Ulm, University of Mannheim, Albert Ludwigs University of Freiburg and University of Heidelberg
Type: Journal Article | Journal: Journal of cancer education : the official journal of the American Association for Cancer Education | Year: 2016

End-of-life care is an essential element of quality cancer care. Nevertheless, a majority of physicians and nurses working at cancer centers feel unprepared for this task. As part of a larger survey study, we investigated what suggestions experienced physicians and nurses have to improve education/training on end-of-life care. In an open question, participants were requested to suggest changes to the end-of-life curriculum for physicians and nurses. Answers to this question were content analyzed using the qualitative data analysis software MAXQDA. Physicians and nurses at 10 cancer centers throughout Baden-Wuerttemberg were surveyed. From the total 1131 survey participants, 675 (483 nurses, 167 physicians, 25 unknown) responded to the open question regarding suggestions for education/training in end-of-life care. Two main categories were inductively developed: (1) format (i.e., structure and method of teaching) and (2) content (i.e., knowledge and know-how required for care of the dying). Regarding format, both professional groups most often wished for more practical experiences with dying patients (e.g., internships at hospices). Regarding content, physicians and nurses most frequently requested (1) more basic information on palliative care, (2) increased skills training in communication, and (3) knowledge of how to appropriately care for patients caregivers. The results of our analysis reflect already trained physicians and nurses interest in furthering their knowledge and skills to care for dying patients. The suggestions of experienced physicians and nurses should be integrated into the further development of palliative care curricula.


PubMed | University Medical Center Tuebingen
Type: Journal Article | Journal: Artificial organs | Year: 2016

The catheter-based Impella 5.0 left ventricular assist device is a powerful and less invasive alternative for patients in cardiogenic shock. The use as second-line therapy in patients with precedent extracorporeal life support (ECLS) has not been described before now. We analyzed our experience of consecutive patients treated with this alternative strategy. From April 2014 to December 2014, eight patients had been implanted as a second-line option after ECLS support. The reason for the change from ECLS to Impella 5.0 was absence of cardiac recovery for primary weaning and complications of ECLS therapy. The mean time of ECLS support prior to Impella implantation was 127 days. The implantation of the Impella 5.0/CP was technically successful in all patients, and the ECLS could be explanted in all eight patients who received Impella implantation as a second-line treatment. The second-line Impella 5.0 therapy resulted in two patients who turned into left ventricular assist device (LVAD) candidates, two primary weaning candidates, and four patients who died in the setting of sepsis or absent cardiac recovery and contraindications for durable LVAD therapy. Thereby, the overall hospital discharge survival as well as the 180-day survival was 50% for Impella 5.0 implantations as second-line procedure after ECLS. The latest follow-up survival of this second-line strategy after ECLS was three out of eight, as one patient died after 299 days of LVAD support due to sepsis. The use of Impella 5.0 constitutes a possible second-line therapeutic option for those patients who do not show cardiac recovery during prolonged ECLS support or suffer from complications of ECLS therapy. This treatment allows additional time for decisions regarding cardiac recovery or indication for durable LVAD therapy.


PubMed | University of Tübingen, Friedrich - Schiller University of Jena and University Medical Center Tuebingen
Type: | Journal: Pharmacological research | Year: 2015

5-Lipoxygenase (5-LO), the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) from arachidonic acid, is regulated by androgens in human neutrophils and monocytes accounting for sex differences in LT formation. Here we show that progesterone suppresses the synthesis of 5-LO metabolites in human primary monocytes. 5-LO product formation in monocytes stimulated with Ca(2+)-ionophore A23187 or with lipopolysaccharide/formyl peptide was suppressed by progesterone at concentrations of 10-100 nM in cells from females and at 1 M in cells from males. Progesterone down-regulated 5-LO product formation in a rapid and reversible manner, but did not significantly inhibit 5-LO activity in cell-free assays using monocyte homogenates. Also, arachidonic acid release and its metabolism to other eicosanoids in monocytes were not significantly reduced by progesterone. The inhibitory effect of progesterone on LTs was still observed when mitogen-activated protein kinases were pharmacologically blocked, stimulatory 1-oleoyl-2-acetyl-sn-glycerol was exogenously supplied, or extracellular Ca(2+) was removed by chelation. Instead, suppression of PKA by means of two different pharmacological approaches (i.e. H89 and a cell-permeable PKA inhibitor peptide) prevented inhibition of 5-LO product generation by progesterone, to a similar extent as observed for the PKA activators prostaglandin E2 and 8-Br-cAMP, suggesting the involvement of PKA. In summary, progesterone affects the capacity of human primary monocytes to generate 5-LO products and, in addition to androgens, may account for sex-specific effects on pro-inflammatory LTs.

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