Characterization of two major urinary metabolites of the PPARδ-agonist GW1516 and implementation of the drug in routine doping controls

Since January 2009, the list of prohibited substances and methods of doping as established by the World Anti-Doping Agency includes new therapeutics such as the peroxisome-proliferator-activated receptor (PPAR)-delta agonist GW1516, which is categorized as a gene doping substance. GW1516 has completed phase II and IV clinical trials regarding dyslipidemia and the regulation of the lipoprotein transport in metabolic syndrome conditions; however, its potential to also improve athletic performance due to the upregulation of genes associated with oxidative metabolism and a modified substrate preference that shifted from carbohydrate to lipid consumption has led to a ban of this compound in elite sport. In a recent report, two presumably mono-oxygenated and bisoxygenated urinary metabolites of GW1516 were presented, which could serve as target analytes for doping control purposes after full characterization. Hence, in the present study, phase I metabolism was simulated by in vitro assays employing human liver microsomal fractions yielding the same oxygenation products, followed by chemical synthesis of the assumed structures of the two abundant metabolic reaction products. These allowed the identification and characterization of mono-oxygenated and bisoxygenated metabolites (sulfoxide and sulfone, respectively) as supported by high-resolution/high-accuracy mass spectrometry with higher-energy collision-induced dissociation, tandem mass spectrometry, and nuclear magnetic resonance spectroscopy. Since urine samples have been the preferred matrix for doping control purposes, a method to detect the new target GW1516 in sports drug testing samples was developed in accordance to conventional screening procedures based on enzymatic hydrolysis and liquid–liquid extraction followed by liquid chromatography, electrospray ionization, and tandem mass spectrometry. Validation was performed for specificity, limit of detection (0.1 ng/ml), recovery (72%), intraday and interday precisions (7.7–15.1%), and ion suppression/enhancement effects (<10%).     

Shear-excited sound in magnetic fluid

Perceptible sound is shown to be excited in ferrofluids by the shear motion of a rigid plate, if the fluid is exposed to a magnetic field oblique both to the plate and to the direction of propagation. This is in contrast to other fluids, including anisotropic ones such as nematic liquids.     

Study on Planar Whispering Gallery Dielectric Resonators. I. General Properties

Several basic properties of homogeneous planar Whispering Gallery dielectric resonators are investigated through a general approach. In particular the values for the minimum and maximum allowed radius, defined by irradiation and dielectric losses, respectively, are obtained in terms of the complex dielectric constant of the involved media. The same approach is employed in the analysis of the limit allowed frequencies of a fixed family of mode, leading to the definition of the ideal frequency band. The role of the transverse mode is then discussed, and the effective frequency band is introduced and determined both in simple disc and circular ring resonators. The extension of the effective band is limited at least by a factor 3, in terms of decades, in comparison to the extension of the ideal one; this limitation, due to the presence of transverse modes, can be overcome using suitable designed nonhomogeneous resonators, as discussed in a following companion paper.     

Application of high-resolution magic-angle spinning NMR spectroscopy to define the cell uptake of MRI contrast agents

A new method, based on proton high-resolution magic-angle spinning ((1)H HR-MAS) NMR spectroscopy, has been employed to study the cell uptake of magnetic resonance imaging contrast agents (MRI-CAs). The method was tested on human red blood cells (HRBC) and white blood cells (HWBC) by using three gadolinium complexes, widely used in diagnostics, Gd-BOPTA, Gd-DTPA, and Gd-DOTA, and the analogous complexes obtained by replacing Gd(III) with Dy(III), Nd(III), and Tb(III) (i.e., complexes isostructural to the ones of gadolinium but acting as shift agents). The method is based on the evaluation of the magnetic effects, line broadening, or induced lanthanide shift (LIS) caused by these complexes on NMR signals of intra- and extracellular water. Since magnetic effects are directly linked to permeability, this method is direct. In all the tests, these magnetic effects were detected for the extracellular water signal only, providing a direct proof that these complexes are not able to cross the cell membrane. Line broadening effects (i.e., the use of gadolinium complexes) only allow qualitative evaluations. On the contrary, LIS effects can be measured with high precision and they can be related to the concentration of the paramagnetic species in the cellular compartments. This is possible because the HR-MAS technique provides the complete elimination of bulk magnetic susceptibility (BMS) shift and the differentiation of extra- and intracellular water signals. Thus with this method, the rapid quantification of the MRI-CA amount inside and outside the cells is actually feasible.     

Lengths of radii under conformal maps of the unit disc

If is the set of endpoints of radii which have length greater than or equal to under a conformal map of the unit disc, then as for the logarithmic capacity of . The exponent is sharp.

     

On Overspill Principles and Axiom Schemes for Bounded Formulas

We study the theories I?_n, L?_n and overspill principles for ?_n formulas. We show that IE_n ? L?_n ? I?_n, but we do not know if I?_n L?_n. We introduce a new scheme, the growth scheme Crγ, and we prove that L?_n ? Cr?_n? I?_n. Also, we analyse the utility of bounded collection axioms for the study of the above theories. Mathematics Subject Classification: 03F30, 03H15.     

Su un problema unidimensionale di diffusione in un mezzo a contorno mobile con condizioni ai limiti non lineari

Summary It is considered a one dimensional heat diffusion probelm in a medium bounded by two parallel planes, x=0 and x=s(t), with a temperature specification on the moving face and a nonlinear relationship between the heat flux and the temperature on the other one. Existence, uniquenesses and computability of the solution are investigated. Continuous and monotone dependence on the data and related properties are also studied. The case s(0)=0 is then widely discussed. The class of boundary problems for which these results hold seems to be very wide.

---

---

Entrata in Redazione il 9 ottobre 1971.

---

Lavoro eseguito nell'ambito dell'attività del Gruppo Nazionale per la Fisica Matematica del C.N.R.     

X-ray structure of trichloro-oxo-(N-pyridylmethylene-N′-salicyloylhydrazine-NO)molybdenum(V) · acetonitrile (1/1). An example of isomerization by complexation

Summary The synthesis, i.r. spectrum and x-ray crystal structure of the title, complex are described, Crystals are monoclinic space groupP 2₁/n, witha = 19.901(7),b = 13.163(8),c = 7.273(6) A, = 90.58(5)° Z = 4, The structure was solved from diffractometer data by direct methods and refined by least-squares techniques toR = 0.053 for 923 independent reflections. The complex has a distortedmer-octahedral geometry [Mo-O = 1,70(1), 2.15(1), Mo-Cl = 2.340(7), 1.352(7), 2.280(7), Mo-N = 2.19(2) A], The starting ligand Hsip, which is in theE configuration when free and in a number of metal complexes where it is terdentate, assumes here theZ configuration and is hiclentate.