A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Light-induced electron spin polarization in the ground state of water-soluble copper porphyrins

Light-induced spin-polarized transient EPR spectra are reported for several water-soluble copper porphyrins. The spectra are assigned to the doublet ground state, with emissive spin polarization resulting from photoexcitation and subsequent electronic relaxation. In contrast to other systems for which polarization of a doublet ground state has been observed, the exchange interactions in the copper porphyrins are strong and the geometry is fixed. It is proposed that intersystem crossing from the photoexcited trip-doublet to the trip-quartet state can lead to net polarization of the spin system and that this polarization is maintained during electronic decay, possibly via charge-transfer and exciplex states. The intensity of the observed spin polarization is essentially independent of the molecular orientation in the external field, but is strongly dependent on the nature of the charged peripheral groups. Possible reasons for this behavior are discussed.     

Effects of citrate on the different phases of calcium oxalate crystallization

Urinary citrate appears to be an important factor in the crystallization process of calcium oxalate and calcium phosphate. The urinary excretion of citrate was found to be significantly lower in patients with calcium oxalate stone disease as compared with normal subjects, and about 30 per cent of the calcium stone formers can be considered as hypocitraturic. The lowest excretion of citrate was recorded in urine collected during the night. Citrate has significant effects on supersaturation with respect to both calcium oxalate and calcium phosphate, it also inhibits the growth of these crystals. In addition, citrate appears to be capable of inhibiting the aggregation of crystals composed of calcium oxalate, brushite, and hydroxyapatite. The heterogenous growth of calcium oxalate on calcium phosphate is also counteracted by citrate. As a consequence of the crucial role of citrate in these processes, stone prevention with alkaline citrate has become an attractive form of treatment in patients with recurrent stone formation. Single evening dose administration of sodium potassium citrate resulted in an of sodium potassium citrate resulted in an increased excretion of citrate, reduced levels of the calcium/citrate ratio as well as supersaturation with respect to calcium oxalate and a decreased rate of stone formation. However, conflicting results of stone preventive treatment with alkaline citrate have been reported by different groups, and long-term follow-up of patients treated in a randomized way is necessary to definitely assess the efficacy of alkaline citrate.     

International legislation on trace elements as contaminants in food: a review

Environmental contaminants such as trace elements may be present in all foods. Foods, raw materials and ingredients for food production are to an increasing extent traded across borders. Hence, there is a need for international legislation on trace elements as contaminants in food. In 1961, the FAO and WHO established the Codex Alimentarius to elaborate international food legislation. Contaminants in food are handled by the Codex Committee for Food Additives and Contaminants (CCFAC). The Codex Alimentarius system for developing legislation concerning trace elements as contaminants in food is based upon the Codex General Standard for Contaminants and Toxins in Food (GSCTF). By October 2001, the principles for setting maximum limits (MLs) for contaminants in food are agreed, and work is in progress on MLs for trace elements such as lead and cadmium in the various food categories. The status for the proposals is presented and discussed. The EU Regulation 466/2001 of 8 March 2001 sets MLs for lead and cadmium in various foods. This regulation will apply from 5 April 2002. The EU regulation is more detailed but similar to the Codex draft standards for lead and cadmium in food. In future, legislators and administrators in the Codex and EU and analytical chemists will discuss how to use more and better analytical data as risk-management tools to protect public health. Trace elements' speciation is an important aspect of this discussion.     

Intramolecular crosslinking of poly(vinyl alcohol)

Poly(vinyl alcohol) is crosslinked in dilute solution (c=0.1 wt%) with glutaraldehyde. The reaction product is characterized by viscometry and gel permeation chromatography (g.p.c.). The intrinsic viscosity decreases with increasing degree of crosslinking and does not depend on temperature. G.p.c. reveals that the reaction product is not homogeneous, but consists of a mixture of particles with different sizes, possibly both intra- and intermolecularly crosslinked molecules. The intramolecularly crosslinked molecules are smaller in size than the initial polymer molecules and their size depends on the degree of crosslinking. They possess a narrow particle size distribution even if the initial polymer sample had a broad molecular weight distribution.     

Miniature in vivo robots for remote and harsh environments

Long-term human space exploration will require contingencies for emergency medical procedures including some capability to perform surgery. The ability to perform minimally invasive surgery (MIS) would be an important capability. The use of small incisions reduces surgical risk, but also eliminates the ability of the surgeon to view and touch the surgical environment directly. Robotic surgery, or telerobotic surgery, may provide emergency surgical care in remote or harsh environments such as space flight, or extremely forward environments such as battlefields. However, because current surgical robots are large and require extensive support personnel, their implementation has remained limited in forward environments, and they would be difficult, or impossible, to use in space flight or on battlefields. This paper presents experimental analysis of miniature fixed-base and mobile in vivo robots to support MIS surgery in remote and harsh environments. The objective is to develop wireless imaging and task-assisting robots that can be placed inside the abdominal cavity during surgery. Such robots will provide surgical task assistance and enable an on-site or remote surgeon to view the surgical environment from multiple angles. This approach is applicable to long-duration space flight, battlefield situations, and for traditional medical centers and other remote surgical locations.     

Consumption of reduced-fat products: effects on parameters of anti-oxidative capacity

Plasma levels of fibrinogen, factor VIIc and prothrombin fragment F1 + 2, a marker of thrombin generation in vivo, were studied in 68 subjects with serum total cholesterol (TC) levels between 135 and 349 mg/dl but without clinical evidence of cardiovascular disease and other atherosclerotic risk factors. F1 + 2 plasma levels were directly correlated with TC (p < 0.0004), low-density lipoprotein cholesterol (LDL-C; p < 0.0018) and factor VIIc (p < 0.024). Thirty-five subjects with TC greater than 249 mg/dl (median value of the whole group) showed higher levels of F1 + 2 (p < 0.0001) and fibrinogen (p < 0.0015) than those with TC lower than 249 mg/dl. In subjects with TC > 249 mg/dl and F1 + 2 > 1.2 nM (median value of the whole group), a cholesterol-lowering drug (simvastatin) was able to reduce F1 + 2 (p < 0.009) as well as TC and LDL-C. This study shows a relationship between serum cholesterol and the rate of thrombin generation supporting the hypothesis that a hypercoagulable state may occur in hypercholesterolemic subjects before the onset of clinical evidence of atherosclerotic cardiovascular disease.     

Zur Frage der Elastizität,der Beanspruchung und der Festigkeit warmbetriebener Rohrleitungen

Zusammenfassung Die Entwicklung der Dampfkraftanlagen zu immer h?heren Temperaturen, Drücken und Leistungen zwingt den Rohrleitungsbauer, sich noch eingehender als bisher mit den Fragen der Elastizit?t, der Beanspruchung und der Festigkeit der Rohrleitung zu besch?ftigen. Zu einigen der wesentlichen Fragen werden im folgenden rechnerische und experimentelle Beitr?ge mitgeteilt. VDI