Termination of pregnancy in the second trimester - the course of different therapy regimens.

OBJECTIVES: To compare two prostaglandin analogs and two application intervals between mifepristone and the prostaglandin analog administration on the time to abortion in second trimester termination of pregnancy. Other endpoints were live birth rate and fetal lifetime after expulsion. METHODS: Retrospective data of 373 abortions performed were evaluated. Four medical induction subgroups and two feticide subgroups were considered. The definition criteria of the subgroups were the choice of administered prostaglandin analog (misoprostol vs. sulprostone) and the time interval between mifepristone and prostaglandin analog administration (48 vs. 24 h). The outcome parameters were the time to complete uterine evacuation (TCUE), the live birth rate and duration of fetal life. RESULTS: In the misoprostol subgroups, the median TCUE was 1.6 h longer in the 24-h group than in the 48-h group (p=0.950). In the sulprostone subgroups, the median TCUE was 1.9 h shorter in the 24-h group than in the 48-h group (p=0.950). The median TCUE was shorter for sulprostone than for misoprostol in all six subgroups (p<0.001). The rate of fetal live births ranged between 13.6 and 15.9% within the medical induction subgroups (p=0.969). The median fetal lifetime was slightly shorter in the sulprostone groups than in the misoprostol groups (p=0.563). CONCLUSIONS: Both application intervals and prostaglandin analogs are similarly effective. The therapy regime should be adapted to the personal preferences of the woman, the situational and clinical conditions.

Identifying new lead structures to enhance tolerance towards drought stress via high-throughput screening giving crops a quantum of solace.

Novel synthetic lead structures interacting with RCAR/(PYR/PYL) receptor proteins were identified based on the results of a high-throughput screening campaign of a large compound library followed by focused SAR studies of the three most promising hit clusters. Whilst indolinylmethyl sulfonamides 8y,z and phenylsulfonyl ethylenediamines 9y,z showed strong affinities for RCAR/ (PYR/PYL) receptor proteins in wheat, thiotriazolyl acetamides 7f,s exhibited promising efficacy against drought stress in vivo (wheat, corn and canola) combined with confirmed target interaction in wheat and arabidopsis thaliana. Remarkably, binding affinities of several representatives of 8 and 9 were on the same level or even better than the essential plant hormone abscisic acid (ABA).

Diene hydroaminomethylation via ruthenium-catalyzed C-C bond forming transfer hydrogenation: beyond carbonylation.

Under the conditions of ruthenium catalyzed transfer hydrogenation using 2-propanol as terminal reductant, 1,3-dienes engage in reductive C-C coupling with formaldimines obtained in situ from 1,3,5-tris(aryl)-hexahydro-1,3,5-triazines to form homoallylic amines. Deuterium labelling studies corroborate a mechanism involving reversible diene hydroruthenation to form an allylruthenium complex that engages in turn-over limiting imine addition. Protonolysis of the resulting amidoruthenium species releases product and delivers a ruthenium alkoxide, which upon ß-hydride elimination closes the catalytic cycle. These transformations, which include enantioselective variants, represent the first examples of diene hydroaminomethylation.

Diastereo- and Enantioselective Iridium Catalyzed Coupling of Vinyl Aziridines with Alcohols: Site-Selective Modification of Unprotected Diols and Synthesis of Substituted Piperidines.

The chiral cyclometalated π-allyliridium ortho-C,O-benzoate complex (R)-Ir-VIb derived from [Ir(cod)Cl]2, allyl acetate, 4-cyano-3-nitro-benzoic acid, and (R)-MeO-BIPHEP catalyzes the coupling of N-(p-nitrophenylsulfonyl) protected vinyl aziridine 3a with primary alcohols 1a-1l to furnish branched products of C-C bond formation 4a-4l with good levels of anti-diastereo- and enantioselectivity. In the presence of 2-propanol, but under otherwise identical conditions, vinyl aziridine 3a and aldehydes 2a-2l engage in reductive coupling to furnish an equivalent set of adducts 4a-4l with roughly equivalent levels of anti-diastereo- and enantioselectivity. Using enantiomeric iridium catalysts, vinyl aziridine 3a reacts with unprotected chiral 1,3-diols 1m-1o in a site-selective manner to deliver the diastereomeric products of C-allylation syn-4m, -4n, -4o and anti-4m, -4n, -4o, respectively, with good isolated yields and excellent levels of catalyst-directed diastereoselectivity. These adducts were directly converted to the diastereomeric 2,4,5-trisubstituted piperidines syn-5m, -5n, -5o and anti-5m, -5n, -5o.

Total and semi-syntheses of antimicrobial thuggacin derivatives.

The total and semi-synthesis of 13 new macrolactones derived from thuggacin, which is a secondary metabolite from the myxobacterium Sorangium cellulosum, are reported. The thuggacins have attracted much attention due to their strong antibacterial activity, particularly towards Mycobacterium tuberculosis. This study focuses on 1) thuggacin derivatives that cannot equilibrate by transacylation between the three natural thuggacins A-C, 2) the roles of the thiazole ring, and 3) the hexyl side chain at C2. Semi-synthetic O-methylation at C17 suppressed the transacylations without a substantial loss of antibacterial activity. Exchanging the C17-C25 side chain for simplified hydrophobic chains led to complete loss of antibacterial activity. Exchange of the thiazole by an oxazole ring or removal of the hexyl side chain at C2 had no substantial effect on the biological properties.

Concomitant inhibition of primary equine bronchial fibroblast proliferation and differentiation by selective ß2-adrenoceptor agonists and dexamethasone.

Altered airway cell proliferation plays an important role in the pathogenesis of human bronchial asthma and chronic obstructive pulmonary disease (COPD) as well as the equine recurrent airway obstruction (RAO) with consistent changes, i.e. narrowing the airway wall, explained by proliferation and differentiation of fibroblasts. In permanent cell lines, it has been suggested that ß2-adrenoceptor agonists and glucocorticoids regulate cell proliferation via the ß2-adrenoceptor pathway; indeed, no study was carried out in fresh isolated primary equine bronchial fibroblasts (EBF). We characterized the ß-adrenoceptors in EBF, and compared effects of long-acting (clenbuterol) and short-acting (salbutamol and isoproterenol) ß2-agonists and dexamethasone on proliferation, differentiation and collagen synthesis. High density (Bmax; 5037±494 sites/cell) of ß2-adrenoceptor subtype was expressed in EBF. ß2-agonists inhibited concentration-dependently EBF proliferation with potency of clenbuterol>salbutamol ¼isoproterenol which was inhibited by ICI 118.551 and propranolol but not by CGP 20712A. In contrast, dexamethasone alone inhibited less EBF proliferation, but the effect was high when dexamethasone was combined with ß2-agonists. Transforming growth factor-ß1 (TGF-ß1) increased transformation of fibroblasts into myofibroblasts, which was inhibited by clenbuterol and dexamethasone alone and drug combination resulted in high inhibition rate. Collagen synthesis in EBF was rather hampered by dexamethasone than by ß-agonists. Collectively, the expression of ß2-adrenoceptor subtype in EBF and the anti-proliferative effect of clenbuterol suggest that ß2-adrenoceptors are growth inhibitory and anti-fibrotic in EBF. These ß2-agonist effects in EBF were synergistically enhanced by dexamethasone, providing the additive effects of glucocorticoids to counteract airway remodelling and morbidity of asthma and RAO.

Comparative study of the effects of fetal bovine serum versus horse serum on growth and differentiation of primary equine bronchial fibroblasts.

BACKGROUND: Airway fibroblasts have become a critical addition to all facets of structural lung tissue changes such as in human asthma and chronic obstructive pulmonary disease, but little is known about their role in the equine recurrent airway obstruction, a disease that resembles to the human asthma. Since the equine bronchial fibroblasts (EBF) have not been isolated and characterized yet, the use of defined medium was investigated. RESULTS: Primary EBF were cultured on non-collagen coated flasks without serum or in the presence of fetal bovine serum (FBS) or horse serum (HS) or in serum depleted medium. EBF cultured in serum-free basal media and those serum deprived were not able to proliferate and even exhibited considerable cell death. In media containing FBS or HS, proliferation of the cells was reproducible between different primary cultures and cells demonstrated expression of vimentin. Large variations were found in the ability of FBS and HS to support growth and differentiation of EBF in monolayer culture. Indications of growth-promoting actions, increasing passage number as well as maintaining fibroblast morphology were found rather in FBS than in HS. EBF culturing in HS needed longer doubling and confluence time. The protein content of the cell pellets was higher in EBF cultured in medium containing HS than FBS. Alpha-smooth muscle actin seemed to be less expressed in EBF cultured in medium containing FBS than those in HS. CONCLUSIONS: In sum, serum addition to basal EBF medium enhanced EBF differentiation into myofibroblasts, and these findings are useful to develop in vitro fibroblast culture models that mimic in vivo physiological processes and to study airway disease mechanisms and remodeling.

Targeting heat-shock-protein 90 (Hsp90) by natural products: geldanamycin, a show case in cancer therapy.

Covering 2005 to 2013. In this review recent progress in the development of heat shock proteins (Hsp90) in oncogenesis is illuminated. Particular emphasis is put on inhibitors such as geldanamycin and analogues that serve as a natural product show case. Hsp90 has emerged as an important target in cancer therapy and/or against pathogenic cells which elicit abnormal Hsp patterns. Competition for ATP by geldanamycin and related compounds abrogate the chaperone function of Hsp90. In this context, this account pursues three topics in detail: a) Hsp90 and its biochemistry, b) Hsp90 and its role in oncogenesis and c) strategies to create compound libraries of structurally complex inhibitors like geldanamycin on which SAR studies and the development of drugs that are currently in different stages of clinical testing rely.

Growth and differentiation of primary and passaged equine bronchial epithelial cells under conventional and air-liquid-interface culture conditions.

BACKGROUND: Horses develop recurrent airway obstruction (RAO) that resembles human bronchial asthma. Differentiated primary equine bronchial epithelial cells (EBEC) in culture that closely mimic the airway cells in vivo would be useful to investigate the contribution of bronchial epithelium in inflammation of airway diseases. However, because isolation and characterization of EBEC cultures has been limited, we modified and optimized techniques of generating and culturing EBECs from healthy horses to mimic in vivo conditions. RESULTS: Large numbers of EBEC were obtained by trypsin digestion and successfully grown for up to 2 passages with or without serum. However, serum or ultroser G proved to be essential for EBEC differentiation on membrane inserts at ALI. A pseudo-stratified muco-ciliary epithelium with basal cells was observed at differentiation. Further, transepithelial resistance (TEER) was more consistent and higher in P1 cultures compared to P0 cultures while ciliation was delayed in P1 cultures. CONCLUSIONS: This study provides an efficient method for obtaining a high-yield of EBECs and for generating highly differentiated cultures. These EBEC cultures can be used to study the formation of tight junction or to identify epithelial-derived inflammatory factors that contribute to lung diseases such as asthma.