Bayesian decision procedures for dose-escalation based on evidence of undesirable events and therapeutic benefit.

In this paper, Bayesian decision procedures are developed for dose-escalation studies based on bivariate observations of undesirable events and signs of therapeutic benefit. The methods generalize earlier approaches taking into account only the undesirable outcomes. Logistic regression models are used to model the two responses, which are both assumed to take a binary form. A prior distribution for the unknown model parameters is suggested and an optional safety constraint can be included. Gain functions to be maximized are formulated in terms of accurate estimation of the limits of a therapeutic window or optimal treatment of the next cohort of subjects, although the approach could be applied to achieve any of a wide variety of objectives. The designs introduced are illustrated through simulation and retrospective implementation to a completed dose-escalation study. Copyright © 2006 John Wiley & Sons, Ltd.

Effect of dietary fish oil on biohydrogenation of fatty acids and milk fatty acid content in cows

Mechanisms underlying milk fat conjugated linoleic acid (CLA) responses to supplements of fish oil were investigated using five lactating cows each fitted with a rumen cannula in a simple experiment consisting of two consecutive 14-day experimental periods. During the first period cows were offered 18 kg dry matter (DM) per day of a basal (B) diet formulated from grass silage and a cereal based-concentrate (0.6 : 0.4; forage : concentrate ratio, on a DM basis) followed by the same diet supplemented with 250 g fish oil per day (FO) in the second period. The flow of non-esterified fatty acids leaving the rumen was measured using the omasal sampling technique in combination with a triple indigestible marker method based on Li-Co-EDTA, Yb-acetate and Cr-mordanted straw. Fish oil decreased DM intake and milk yield, but had no effect on milk constituent content. Milk fat trans-11C(18:1), total trans-C-18:1, cis-9 trans-11 CLA, total CLA, C-18 :2 (n- 6) and total C-18:2 content were increased in response to fish oil from 1.80, 4.51, 0.39, 0. 56, 0.90 and 1.41 to 9.39, 14.39, 1.66, 1.85, 1.25 and 4.00 g/100 g total fatty acids, respectively. Increases in the cis-9, trans-11 isomer accounted for proportionately 0.89 of the CLA response to fish oil. Furthermore, fish oil decreased the flow of C-18:0 (283 and 47 g/day for B and FO, respectively) and increased that of trans-C-18:1 fatty acids entering the omasal canal (38 and 182 g/day). Omasal flows of trans-C-18:1 acids with double bonds in positions from delta-4 to -15 inclusive were enhanced, but the effects were isomer dependent and primarily associated with an increase in trans-11C(18:1) leaving the rumen (17.1 and 121.1 g/day for B and FO, respectively). Fish oil had no effect on total (4.36 and 3.50 g/day) or cis-9, trans-11 CLA (2.86 and 2.08 g/day) entering the omasal canal. Flows of cis-9, trans-11 CLA were lower than the secretion of this isomer in milk. Comparison with the transfer of the trans-9, trans-11 isomer synthesized in the rumen suggested that proportionately 0.66 and 0.97 of cis-9, trans-11 CLA was derived from endogenous conversion of trans-11 C-18:1 in the mammary gland for B and FO, respectively. It is concluded that fish oil enhances milk fat cis-9, trans-11 CLA content in response to increased supply of trans-11 C-18:1 that arises from an inhibition of trans C-18:1 reduction in the rumen.

Comparison of the volatile compositions and flavour properties of cantaloupe, Galia and honeydew muskmelons

Aroma compounds were extracted from three cultivars of muskmelon (Cucumis melo L.) by solid-phase microextraction and analysed by gas chromatography-mass-spectrometry. Sulfur-containing esters and compounds containing a straight six-carbon chain were present at high concentrations in cantaloupe melons. Compounds containing a straight nine-carbon chain were at high concentrations in honeydew melons. Methyl esters were present at the highest levels in Galia melons. The sensory properties of the three melons were also compared. Cantaloupe melons were associated with sweet, floral and fruity aromas and a persistent aftertaste. Galia melons possessed the strongest cucumber-like flavours, while cucumber aroma and sweet flavour scored highly in honeydew melons. (c) 2005 Elsevier Ltd. All rights reserved.

Synthesis, X-ray crystal structures and properties of complex salts and sterically crowded heteroleptic complexes of group 10 metal ions with aromatic sulfonyl dithiocarbimates and triphenylphosphine ligand

Two new complex salts of the form (Bu4N)(2)[Ni(L)(2)] (1) and (Ph4P)(2)[Ni(L)(2)] (2) and four heteroleptic complexes cis-M(PPh3)(2)(L) [M = Ni(II) (3), Pd(II) (4), L = 4-CH3OC6H4SO2N=CS2] and cis-M(PPh3)(2)(L') [M = Pd(II) (5), Pt(II) (6), L' = C6H5SO2N=CS2] were prepared and characterized by elemental analyses, IR, H-1, C-13 and P-31 NMR and UV-Vis spectra, solution and solid phase conductivity measurements and X-ray crystallography. A minor product trans-Pd(PPh3)(2)(SH)(2), 4a was also obtained with the synthesis of 4. The NiS4 and MP2S2 core in the complex salts and heteroleptic complexes are in the distorted square-plane whereas in the trans complex, 4a the centrosymmetric PdS2P2 core is perforce square planar. X-ray crystallography revealed the proximity of the ortho phenyl proton of the PPh3 ligand to Pd(II) showing rare intramolecular C-H center dot center dot center dot Pd anagostic binding interactions in the palladium cis-5 and trans-4a complexes. The complex salts with sigma(rt) values similar to 10 (5) S cm (1) show semi-conductor behaviors. The palladium and platinum complexes show photoluminescence properties in solution at room temperature.

A randomised trial to investigate the effects of acute consumption of a blackcurrant juice drink on markers of vascular reactivity and bioavailability of anthocyanins in human subjects

Objective: To study the bioavailability of anthocyanins and the effects of a 20% blackcurrant juice drink on vascular reactivity, plasma antioxidant status and other CVD risk markers. Subjects/Methods: The study was a randomised, cross over, double blind, placebo controlled acute meal study. Twenty healthy volunteers (11 females 9 males) were recruited, and all subjects completed the study. Fasted volunteers consumed a 20% blackcurrant juice drink (250 ml) or a control drink following a low-flavonoid diet for the previous 72 hours. Vascular reactivity was assessed at baseline and 120 mins after juice consumption by Laser Doppler Imaging (LDI). Plasma and urine samples were collected periodically over an 8 hour period for analysis, with a final urine sample collected at 24h. The cross over was performed after a 4-week washout. Results: There were no significant effects of the 20% blackcurrant juice drink on acute measures of vascular reactivity, biomarkers of endothelial function or lipid risk factors. Consumption of the test juice caused increases in plasma vitamin C (P=0.006), and urinary anthocyanins (P<0.001). Delphinidin-3-rutinoside and cyanidin-3-rutinoside were the main anthocyanins excreted in urine with delphinidin-3-glucoside also detected. The yield of anthocyanins in urine was 0.021 ± 0.003% of the dietary intake of delphinidin glycosides and 0.009 ± 0.002 % of the dietary intake of cyanidin glycosides. Conclusions: The juice consumption did not have a significant effect on vascular reactivity. Anthocyanins were present at low concentrations in the urine, and microbial metabolites of flavonoids were detected in plasma after juice consumption.

Spectroscopic properties of alkenylferrocenes; crystal and molecular structure of (Z)-(1,2-diphenylethenyl)ferrocene

Studies of the 1H n.m.r. and electronic spectra of a series of alkenylferrocenes including (E) and (Z) stereoisomers of various styrylferrocenes, have provided methods of structure elucidation. Crystals of the title compound are monoclinic, space group P21/c with Z= 4 in a unit cell of dimensions a= 17.603(2), b= 10.218(2), c= 10.072 Å, β= 103.27(2)°. The structure has been determined by the heavy-atom method from diffractometer data and refind by full-matrix least-squares techniques to R= 0.043 for 2 219 unique reflections.

Getting on top of things: form and meaning in the pseudo-Vergilian Aetna

This article offers a fresh view on the poetics of the pseudo-Vergilian poem Aetna, proposing a carefully planned and executed structure which is supported through a deliberate arrangement of key terms in the poem as well as a network of verbal cross-references

Effects of supplementation with free glutamine and the dipeptide alanyl-glutamine on parameters of muscle damage and inflammation in rats submitted to prolonged exercise

In this study, we investigated the effect of the supplementation with the dipeptide L-alanyl-L-glutamine (DIP) and a solution containing L-glutamine and L-alanine on plasma levels markers of muscle damage and levels of pro-inflammatory cytokines and glutamine metabolism in rats submitted to prolonged exercise. Rats were submitted to sessions of swim training for 6 weeks. Twenty-one days prior to euthanasia, the animals were supplemented with DIP (n = 8) (1.5 g.kg(-1)), a solution of free L-glutamine (1 g.kg(-1)) and free L-alanine (0.61 g.kg(-1)) (G&A, n = 8) or water (control (CON), n = 8). Animals were killed at rest before (R), after prolonged exercise (PE-2 h of exercise). Plasma concentrations of glutamine, glutamate, tumour necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2) and activity of creatine kinase (CK), lactate dehydrogenase (LDH) and muscle concentrations Of glutamine and glutamate were measured. The concentrations of plasma TNF-alpha, PGE2 and the activity of CK were lower in the G&A-R and DIP-R groups, compared to the CON-R. Glutamine in plasma (p < 0.04) and soleus muscle (p < 0.001) was higher in the DIP-R and G&A-R groups relative to the CON-R group. G&A-PE and DIP-PE groups exhibited lower concentrations of plasma PGE2 (p < 0.05) and TNF-alpha (p < 0.05), and higher concert I rations of glutamine and glutamate in soleus (p < 0.001) and gastrocnemius muscles (p < 0.05) relative to the CON-PE group. We concluded that supplementation with free L-glutamine and the dipeptide LL-alanyl-LL-glutamine represents an effective source of glutamine, which may attenuate inflammation biomarkers after periods of training and plasma levels of CK and the inflammatory response induced by prolonged exercise. Copyright (C) 2009 John Wiley & Sons, Ltd.

Structural Aspects of the Distinct Biochemical Properties of Glutaredoxin 1 and Glutaredoxin 2 from Saccharomyces cerevisiae

Glutaredoxins (Grxs) are small (9-12 kDa) heat-stable proteins that are ubiquitously distributed. In Saccharomyces cerevisiae, seven Grx enzymes have been identified. Two of them (yGrx1 and yGrx2) are dithiolic, possessing a conserved Cys-Pro-Tyr-Cys motif. Here, we show that yGrx2 has a specific activity 15 times higher than that of yGrx1, although these two oxidoreductases share 64% identity and 85% similarity with respect to their amino acid sequences. Further characterization of the enzymatic activities through two-substrate kinetics analysis revealed that yGrx2 possesses a lower Km for glutathione and a higher turnover than yGrx1. To better comprehend these biochemical differences, the pK(a) of the N-terminal active-site cysteines (Cys27) of these two proteins and of the yGrx2-C30S mutant were determined. Since the pK(a) values of the yGrx1 and yGix2 Cys27 residues are very similar, these parameters cannot account for the difference observed between their specific activities. Therefore, crystal structures of yGrx2 in the oxidized form and with a glutathionyl mixed disulfide were determined at resolutions of 2.05 and 1.91 angstrom, respectively. Comparisons of yGrx2 structures with the recently determined structures of yGrx1 provided insights into their remarkable functional divergence. We hypothesize that the substitutions of Ser23 and Gln52 in yGrx1 by Ala23 and Glu52 in yGrx2 modify the capability of the active-site C-terminal cysteine to attack the mixed disulfide between the N-terminal active-site cysteine and the glutathione molecule. Mutagenesis studies supported this hypothesis. The observed structural and functional differences between yGrx1 and yGrx2 may reflect variations in substrate specificity. (C) 2008 Elsevier Ltd. All rights reserved.

Conformational Properties of Angiotensin II and Its Active and Inactive TOAC-Labeled Analogs in the Presence of Micelles. Electron Paramagnetic Resonance, Fluorescence, and Circular Dichroism Studies

The interaction between angiotensin II (AII, DRVYIHPF) and its analogs carrying 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) and detergents-negatively charged sodium dodecyl sulfate (SDS) and zwitterionic N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (HPS)-was examined by means of EPR, CD, and fluorescence. EPR spectra of partially active TOAC(1)-AII and inactive TOAC(3)-AII in aqueous solution indicated fast tumbling, the freedom of motion being greater at the N-terminus. Line broadening occurred upon interaction with micelles. Below SDS critical micelle concentration, broader lines indicated complex formation with tighter molecular packing than in micelles. Small changes in hyperfine splittings evinced TOAC location at the micelle-water interface. The interaction with anionic micelles was more effective than with zwitterionic micelles. Peptide-micelle interaction caused fluorescence increase. The TOAC-promoted intramolecular fluorescence quenching was more, pronounced for TOAC(3)-AII because of the proximity between the nitroxide and Tyr(4). CD spectra showed that although both AII and TOAC(1)-AII presented flexible conformations in water, TOAC(3)-AII displayed conformational restriction because of the TOAC-imposed bend (Schreier et al., Biopolymers 2004, 74, 389). In HPS, conformational changes were observed for the labeled peptides at neutral and basic pH. In SDS, all peptides underwent pH-dependent conformational changes. Although the spectra suggested similar folds for All and TOAC(1)-AII, different conformations were acquired by TOAC(3)-AII. The membrane environment has been hypothesized to shift conformational equilibria so as to stabilize the receptor-bound conformation of ligands. The fact that TOAC(3)-AII is unable to acquire conformations similar to those of native AII and partially active TOAC(1)-AII is probably the explanation for its lack of biological activity. (C) 2009 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 92: 525-537, 2009.

A note on convergence of Peck-Shell and Green-Lin mechanisms in the Diamond-Dybvig model

We study the effects of population size in the Peck-Shell analysis of bank runs. We find that a contract featuring equal-treatment for almost all depositors of the same type approximates the optimum. Because the approximation also satisfies Green-Lin incentive constraints, when the planner discloses positions in the queue, welfare in these alternative specifications are sandwiched. Disclosure, however, it is not needed since our approximating contract is not subject to runs.

Structural Aspects of the Distinct Biochemical Properties of Glutaredoxin 1 and Glutaredoxin 2 from Saccharomyces cerevisiae

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Effect of Diets on Biology of Abaris basistriata and Selenophorus seriatoporus (Coleoptera: Carabidae)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)