Signaling of the cytokine interleukin-6 (IL-6) via its soluble IL-6 receptor (sIL-6R) is responsible for the proinflammatory properties of IL-6 and constitutes an attractive therapeutic target, but how the sIL-6R is generated in vivo remains largely unclear. Here, we use liquid chromatography–mass spectrometry to identify an sIL-6R form in human serum that originates from proteolytic cleavage, map its cleavage site between Pro-355 and Val-356, and determine the occupancy of all O- and N-glycosylation sites of the human sIL-6R. The metalloprotease a disintegrin and metalloproteinase 17 (ADAM17) uses this cleavage site in vitro, and mutation of Val-356 is sufficient to completely abrogate IL-6R proteolysis. N- and O-glycosylation were dispensable for signaling of the IL-6R, but proteolysis was orchestrated by an N- and O-glycosylated sequon near the cleavage site and an N-glycan exosite in domain D1. Proteolysis of an IL-6R completely devoid of glycans is significantly impaired. Thus, glycosylation is an important regulator for sIL-6R generation.

Once daily, oral roflumilast 500 microg was comparable with inhaled twice-daily BDP (400 microg/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.

Four gold(I) carbene complexes featuring 4-ferrocenyl-substituted imidazol-2-ylidene ligands were investigated for antiproliferative and antivascular properties. They were active against a panel of seven cancer cell lines, including multidrug-resistant ones, with low micromolar or nanomolar IC (72 h) values, according to their lipophilicity and cellular uptake. The delocalized lipophilic cationic complexes 8 and 10 acted by increasing the reactive oxygen species in two ways: through a genuine ferrocene effect and by inhibiting the thioredoxin reductase. Both complexes gave rise to a reorganization of the F-actin cytoskeleton in endothelial and melanoma cells, associated with a G1 phase cell cycle arrest and a retarded cell migration. They proved antiangiogenic in tube formation assays with endothelial cells and vascular-disruptive on real blood vessels in the chorioallantoic membrane of chicken eggs. Biscarbene complex 10 was also tolerated well by mice where it led to a volume reduction of xenograft tumors by up to 80 %.

To evaluate patient acceptance, optical properties and the clinical feasibility of flexible compared with rigid hysteroscopes, 142 patients undergoing outpatient hysteroscopy were included in a prospective, randomized clinical trial. The flexible hysteroscope was used in 70 patients, and the rigid instrument in 72. At different stages of the hysteroscopy the level of pain experienced by the women was assessed using a 10 cm visual analogue scale. Optical properties characterized by the parameters intrauterine visibility, hysteroscopic view and diagnostic accuracy were ranked by the surgeons using a 5-point scale (1 = excellent to 5 = insufficient), and duration of the hysteroscopy was measured. Hysteroscopy was successful in 87.5 and 100% of patients in the flexible and rigid groups respectively. With the use of rigid telescopes, discomfort at introduction and during the hysteroscopy was significantly greater (median 1.7 versus 0.7, P = 0.003; 3.1 versus 1.2, P < 0.001 respectively), but optical properties were judged to be far superior (P < 0.001 for all three comparisons) and procedure time was significantly shorter (median 70 versus 120 s, P = 0.003). In conclusion, outpatient hysteroscopy seems to be less painful when using flexible telescopes. However, rigid hysteroscopes provide superior optical qualities and permit a more rapid performance with higher success rates at much lower cost.

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