Hepatic failure is commonly associated with anemia, which may result from gastrointestinal bleeding, vitamin deficiency, or liver-damaging diseases, such as infection and alcohol intoxication. At least in theory, anemia during hepatic failure may result from accelerated clearance of circulating erythrocytes. Here we show that bile duct ligation (BDL) in mice leads to severe anemia despite increased reticulocyte numbers. Bilirubin stimulated suicidal death of human erythrocytes. Mechanistically, bilirubin triggered rapid Ca2+ influx, sphingomyelinase activation, formation of ceramide, and subsequent translocation of phosphatidylserine to the erythrocyte surface. Consistent with our in vitro and in vivo findings, incubation of erythrocytes in serum from patients with liver disease induced suicidal death of erythrocytes in relation to their plasma bilirubin concentration. Consistently, patients with hyperbilirubinemia had significantly lower erythrocyte and significantly higher reticulocyte counts compared to patients with low bilirubin levels. Conclusion: Bilirubin triggers suicidal erythrocyte death, thus contributing to anemia during liver disease. (Hepatology 2015;61:275–284)

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Table 2. Preparation of w-ureido D-amino acids Hydantoin o-amino acid Content of ~[ h ] 0 0 n = l '0 n = 2 n = 3 D-alhizziin (101 D-4-ureido-2-aminohutyric acid[ll] 0-ci trulline I1 21 . . n = 4 D-homocitrulline 1131 H 0 H H,N N d S + C O O H I, NH, 0 V 69 73 79 70 > 99 98-99.8 96-99.8 60 m = 1 0 o-w-ureido-AEC [c] 71 98-99.8 m = 2 D-w-carhamoylthialysine 1141 78 98-99.8 [a] Yield of isolated product [YO]. [h] Amount Of D enantiomer [%I, determined by comparison with literature data or by chromatography with the racemic compounds for comparison[l0-14]; the ranges refer to different runs. [c] AEC = S-aminoethylcysteine.Furthermore, we desired to determine the spectrum of substrates accepted by this biocatalyst. Readily obtainable racemic or L-n,w-diamino carboxylic acids were converted into hydantoins analogous to 5['' and subjected to biotransformation (Table 2).This approach provides a series of interesting w-ureido 6-amino acids that are chemically synthesized only with difficulty and are not obtainable at all through fermentation. These examples show the advantages of combining chemical and enzymatic steps in the preparation of enantiomerically pure amino acids unknown in nature. Experimental ProcedureSummary of the synthesis ofo-citrulline (1, C,H,,N,O,, M = 175.19)[15]: A solution of 5 (4 g, 22.8 mmol), prepared according to 191, in water (55 mL) was adjusted to pH 8.4 by addition of concentrated aqueous sodium hydroxide. The solution was then degassed by agitating in a mechanical shaker at 40 "C for 10 min, treated with the bacterial culture (Agrobaclerium radiobacter, 0.5 g) under N,, degassed once again, and then sparged with N,. The vessel was shaken for 24 h at 40 "C under N, at 6 bar and then for 24 h at 40 "C under normal pressure before cooling it and adjusting the pH of the solution to pH9. The solid portion of the culture was separated by centrifugation and the remaining liquid was treated with charcoal to clear the solution. Yield in solution 95%. Isolation was accomplished by filtering the solution through a strongly acidic ion exchanger (Merck, IR 120) and eluting the product with 5 % aqueous NH,. The solution thereby obtained was evaporated and the residue was dissolved in a small amount of water. Addition of ethanol precipitated the product. 3.4g (85%), m.p. 215-218 "C (dec.), [a]:': +22 (c = 2 in 1 N HCI) 'H NMR (250 MHz, D,O): 6 = 3.73 (m, 1 H, Ha), 3.1 (m. 2H, Hy); 1.4-2.0 (2 x m, each 2H, Hfi + H;?.Well over half a century ago, E. Hiickel proposed the (4n + 2)-electron rule for cyclic IT systems. Since then, this simple and fascinating concept"' has stimulated the syntheses of a great variety of novel molecules and molecular ions, which in lab jargon are frequently termed aromatic (Greek: aromatikos = herbal smelling) and which, according to numerous experimental data as well as quantum-chemical results, are distinguished by an energetically favorable electron distribution.['] Deviations from the optimum number of electrons, therefore, should inflict severe perturbations and, as is known f...

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The study shows that networking of deliverers of care for IBD patients with health insurances provides an excellent possibility to optimise medical treatment and can cut down costs significantly.