Microbial xylose reductase, a representative aldo-keto reductase of primary sugar metabolism, catalyzes the NAD(P)H-dependent reduction of D-xylose with a turnover number approximately 100 times that of human aldose reductase for the same reaction. To determine the mechanistic basis for that physiologically relevant difference and pinpoint features that are unique to the microbial enzyme among other aldo/keto reductases, we carried out stopped-flow studies with wild-type xylose reductase from the yeast Candida tenuis. Analysis of transient kinetic data for binding of NAD(+) and NADH, and reduction of D-xylose and oxidation of xylitol at pH 7.0 and 25 degrees C provided estimates of rate constants for the following mechanism: E + NADH right arrow over left arrow E.NADH right arrow over left arrow E.NADH + D-xylose right arrow over left arrow E.NADH.D-xylose right arrow over left arrow E.NAD(+).xylitol right arrow over left arrow E.NAD(+) right arrow over left arrow E.NAD(+) right arrow over left arrow E + NAD(+). The net rate constant of dissociation of NAD(+) is approximately 90% rate limiting for k(cat) of D-xylose reduction. It is controlled by the conformational change which precedes nucleotide release and whose rate constant of 40 s(-)(1) is 200 times that of completely rate-limiting E.NADP(+) --> E.NADP(+) step in aldehyde reduction catalyzed by human aldose reductase [Grimshaw, C. E., et al. (1995) Biochemistry 34, 14356-14365]. Hydride transfer from NADH occurs with a rate constant of approximately 170 s(-1). In reverse reaction, the E.NADH --> E.NADH step takes place with a rate constant of 15 s(-1), and the rate constant of ternary-complex interconversion (3.8 s(-1)) largely determines xylitol turnover (0.9 s(-1)). The bound-state equilibrium constant for C. tenuis xylose reductase is estimated to be approximately 45 (=170/3.8), thus greatly favoring aldehyde reduction. Formation of productive complexes, E.NAD(+) and E.NADH, leads to a 7- and 9-fold decrease of dissociation constants of initial binary complexes, respectively, demonstrating that 12-fold differential binding of NADH (K(i) = 16 microM) vs NAD(+) (K(i) = 195 microM) chiefly reflects difference in stabilities of E.NADH and E.NAD(+). Primary deuterium isotope effects on k(cat) and k(cat)/K(xylose) were, respectively, 1.55 +/- 0.09 and 2.09 +/- 0.31 in H(2)O, and 1.26 +/- 0.06 and 1.58 +/- 0.17 in D(2)O. No deuterium solvent isotope effect on k(cat)/K(xylose) was observed. When deuteration of coenzyme selectively slowed the hydride transfer step, (D)()2(O)(k(cat)/K(xylose)) was inverse (0.89 +/- 0.14). The isotope effect data suggest a chemical mechanism of carbonyl reduction by xylose reductase in which transfer of hydride ion is a partially rate-limiting step and precedes the proton-transfer step.

The technique of atomising liquid metal and compacting the micro-droplets to a billet on a rotating support combines advantages from cast, wrought and powder metallurgical materials. A production rate of several tons per hour requires precisely controlled processing routines. Important process parameters based on processing, manufacturing and application of spray formed material are now developed by fundamental investigations established in projects focused in a special co-operative research program (SFB 372) at the University of Bremen which is funded by the Deutsche Forschungsgemeinschaft (DFG). By this method advanced alloys of high hardness can be formed without inhomogeneities like segregations and pores in the center of the ingot. By example of tool steels the influence of spray forming on microstructure and homogeneity of the elemental distribution is shown.

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This study indicates that in tube-fed insulin-treated type II diabetic patients, the new low-carbohydrate, high MUFA formula results in a more effective glycaemic control than the standard diet, while being comparable in safety.

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SUMMARYAim: To compare the efficacy of simethicone with placebo and the prokinetic cisapride in patients with functional dyspepsia. Methods: One hundred and eighty-five patients with functional dyspepsia were randomized and treated in a double-dummy technique with simethicone (105 mg t.d.s.), cisapride (10 mg t.d.s.) or placebo (t.d.s.). The primary outcome measure was the O'Brien global measure of the patients' rating of 10 upper gastrointestinal symptoms (graded as absent ¼ 0, moderate ¼ 1, severe ¼ 2 or very severe ¼ 3). Outcome measures were assessed at baseline and after 2, 4 and 8 weeks of treatment (intention-to-treat).Results: At 2, 4 and 8 weeks, treatment with simethicone and cisapride yielded significantly (all P values < 0.0001) better improvement of symptoms compared to placebo. Simethicone was significantly better than cisapride after 2 weeks (P ¼ 0.0007), but the differences were not statistically significant after 4 and 8 weeks.Patients treated with simethicone judged the efficacy of their treatment as very good in 46% of cases, compared to 15% and 16% receiving cisapride and placebo, respectively. Conclusions: Simethicone and cisapride were significantly better than placebo for symptom control in patients with functional dyspepsia after 2, 4 and 8 weeks of treatment. Simethicone was also superior to the prokinetic cisapride in the first 2 weeks of treatment.

Long-term tube feeding with a disease-specific enteral formula was safe and well tolerated in type 2 diabetic patients with neurological disorders. When compared with a standard diet, TI requirement decreased significantly with less hypoglycemia whereas FG and AG were significantly lowered, resulting in improved glycemic control.