SummaryAlthoughglucocorticoidsare widelyusedinanumberofinflammatorydisorders associatedwith endothelialand plateletactivation, their effect on the endothelium and platelets in humans remainpoorlydefined.Hence,wemeasuredchanges of aspecific endothelialcellmarker (von Willebrand factor [vWF]) and of a plateletm arker (solubleP -selectin) by infusing therapeutic dosesofdexamethasone (0.04 mg/kg and 1.0mg/kg b.i.d on two days) or placebo into ninehealthymen.Venous citratedplasma was obtainedbeforeinfusion, and at 24 and 48 h. Compared to baselinel evels, we found increasedl evelso fv WF at botht ime points at the higherdose (p=0.011).Plasma levels of sP-selectin rose at 48 hafter the highdose (p=0.017).Human umbilical endothelialcells were culturedinthe presence or absence of de- KeywordsVo nW illebrand factor, P-selectin, dexamethason, randomised controlledtrial xamethasone (0, 0.01, 1 µ M), to determine the possible mechanism forthe increase in vWF.The vWF-mRNA levels as quantifiedbyR T-PCR increased2-fold (p<0.05),and the vWF-concentrations in cell lysates increasedb y3 8% (p<0.05), whereast he vWF-concentrations in the supernatants were unaffected. In summary, highd ose DEXA increasess P-selectin and vWF.The probable underlying mechanismf or thel atterw as aD EXA inducedup-regulationofvWF-mRNA transcription.Together,this indicates thathigh dose glucocorticoidsmay enhancehaemostasis,which could be beneficial undercertain conditions,butwhich mayalsocontributetoadverse vascular events by increasing plateletactivation and vWFdependent thrombosis.

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Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE). Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE. In contrast to published literature, we demonstrate that placenta-associated diamine oxidase (DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels. Cultures of primary EVTs express and secret large amounts of bioactive DAO. ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs. Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels. This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.

The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system.

Background Histaminolytic activity mediated by diamine oxidase (DAO) is present in plasma after induction of severe anaphylaxis in rats, guinea pigs, and rabbits. Heparin released during mast cell degranulation in the gastrointestinal tract might liberate DAO from heparin‐sensitive storage sites. DAO release during anaphylaxis has not been demonstrated in humans. Methods Plasma DAO, tryptase, and histamine concentrations of four severe anaphylaxis events were determined at multiple serial time points in two patients with systemic mastocytosis. The histamine degradation rates were measured in anaphylaxis samples and in pregnancy sera and plasma with comparable DAO concentrations. Results Mean DAO (132 ng/mL) and tryptase (304 ng/mL) concentrations increased 187‐ and 4.0‐fold, respectively, over baseline values (DAO 0.7 ng/mL, tryptase 76 ng/mL) during severe anaphylaxis. Under non‐anaphylaxis conditions, DAO concentrations were not elevated in 29 mastocytosis patients compared to healthy volunteers and there was no correlation between DAO and tryptase levels in mastocytosis patients. The histamine degradation rate of DAO in plasma from mastocytosis patients during anaphylaxis is severely compromised compared to DAO from pregnancy samples. Conclusion During severe anaphylaxis in mastocytosis patients, DAO is likely released from heparin‐sensitive gastrointestinal storage sites. The measured concentrations can degrade histamine, but DAO activity is compromised compared to pregnancy samples. For accurate histamine measurements during anaphylaxis, DAO inhibition is essential to inhibit further histamine degradation after blood withdrawal. Determination of DAO antigen levels might be of clinical value to improve the diagnosis of mast cell activation.