Stroboscopy

The history and principles of stroboscopy are reviewed, and stroboscopic findings during videolaryngoscopy are evaluated in relationship to the rest of the laryngological clinical evaluation to arrive at the bases for a stroboscopic semiology     

A stochastic extra-step quasi-Newton method for nonsmooth nonconvex optimization

In this paper, a novel stochastic extra-step quasi-Newton method is developed to solve a class of nonsmooth nonconvex composite optimization problems. We assume that the gradient of the smooth part of the objective function can only be approximated by stochastic oracles. The proposed method combines general stochastic higher order steps derived from an underlying proximal type fixed-point equation with additional stochastic proximal gradient steps to guarantee convergence. Based on suitable bounds on the step sizes, we establish global convergence to stationary points in expectation and an extension of the approach using variance reduction techniques is discussed. Motivated by large-scale and big data applications, we investigate a stochastic coordinate-type quasi-Newton scheme that allows to generate cheap and tractable stochastic higher order directions. Finally, numerical results on large-scale logistic regression and deep learning problems show that our proposed algorithm compares favorably with other state-of-the-art methods.

     

Mechanisms of stochastic phase locking

Periodically driven nonlinear oscillators can exhibit a form of phase locking in which a well-defined feature of the motion occurs near a preferred phase of the stimulus, but a random number of stimulus cycles are skipped between its occurrences. This feature may be an action potential, or another crossing by a state variable of some specific value. This behavior can also occur when no apparent external periodic forcing is present. The phase preference is then measured with respect to a time scale internal to the system. Models of these behaviors are briefly reviewed, and new mechanisms are presented that involve the coupling of noise to the equations of motion. Our study investigates such stochastic phase locking near bifurcations commonly present in models of biological oscillators: (1) a supercritical and (2) a subcritical Hopf bifurcation, and, under autonomous conditions, near (3) a saddle-node bifurcation, and (4) chaotic behavior. Our results complement previous studies of aperiodic phase locking in which noise perturbs deterministic phase-locked motion. In our study however, we emphasize how noise can induce a stochastic phase-locked motion that does not have a similar deterministic counterpart. Although our study focuses on models of excitable and bursting neurons, our results are applicable to other oscillators, such as those discussed in the respiratory and cardiac literatures. (c) 1995 American Institute of Physics.     

Peroxo and alkylperoxidic molybdenum(VI) complexes as intermediates in the epoxidation of olefins by alkyl hydroperoxides

Novel oxoperoxomolybdenum(VI) complexes with the general formula MoO(O₂)L₂X₂ (III, L = DMF, HMPT) and MoO(O₂)Cl(ON)L(IV, ON) = pyridin-2-carboxylate (Pic), 8-hydroxyquinolinate (Quin) were prepared from the reaction of Ph₃COOH or H₂O₂ with the corresponding cis-dioxo complexes. In the reaction with Ph₃COOH both oxygen atoms of the peroxo moiety were found, by ¹⁸O labeling experiments, to come from the hydroperoxide. The X-ray crystal structure of MoO(O₂)Cl(Pic)(HMPT) revealed a bipyramidal pentagonal surounding with a rather short OO distance (1.41 Å). Complexes III were found to be more reactive than MoO(O₂)₂,HMPT for the epoxidation of olefins (oxidative cleavage products are consecutively formed) but react by the same cyclic peroxymetalation mechanism. The absence of reaction in the case of complexes IV illustrates the necessity for the metal to possess an equatorial releasable coordination site adjacent to the peroxo group for the oxygen transfer to occur. Catalytic oxidation of olefins using Ph₃COOH gave a selectivity in oxygenated products very different from that using t-BuOOH, and ¹⁸O labeling studies showed that alkyl-peroxidic rather than peroxo species are intermediates in this latter reaction. The mechanism of epoxidation of olefins by alkyl hydroperoxides catalyzed by d⁰ metal complexes is discussed.     

Complex formation of uranium(VI) with 4-hydroxy-3-methoxybenzoic acid and related compounds

Summary The complex formation of uranium(VI) with 4-hydroxy-3-methoxybenzoic acid as well as with benzoic acid and 4-hydroxybenzoic acid was studied. In aqueous solution weak carboxylic 1 : 1 complexes, are formed in which the carboxyl group is bidentately coordinated to the metal atom. The logarithmic stability constants of these complexes regarding the reaction of the uranyl ion with the single charged anion of the respective ligands are 2.78±0.02, 2.68±0.04, and 2.71±0.04 at an ionic strength of 0.1 mol/l (NaClO₄) and at 25 °C. Bis(4-hydroxy-3-methoxybenzoato)dioxouranium(VI) was obtained as a crystalline compound if the concentrations of the starting components for the synthesis are increased. The monoclinic compound has a reflections-rich X-ray powder diffraction pattern. The lattice constants are a = 13.662(9) ?, b = 21.293(7) ?, c = 11.213(3) ?, b = 107.49(4), and V = 3111(2) ?.³     

Synthesis and antifolate activity of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine analogues of trimetrexate and piritrexim

2,4-Diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines with di- and trimethoxyaralkyl substitution at the 6-position were synthesized from the N⁶-unsubstituted compound and appropriate aralkyl bromides in N,N-dimethylformamide solution containing a catalytic amount of sodium iodide. An improved method of preparation of 2,4-diamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine from 2-amino-6-benzyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one was also developed, in which N² was protected by reaction with pivalic anhydride and the resulting product was subjected consecutively to reaction with 4-chlorophenylphosphorodichloridate and 1,2,4-triazole, ammonolysis to replace the 4-imidazolido group and remove the N²-pivaloyl group, and catalytic hydrogenolysis to remove the 6-benzyl group. In assays of the ability of the products to inhibit dihydrofolate reductase from Pneumocystis carinii, and Toxoplasma gondii, and rat liver the most active of the compounds tested was 2,4-diamino-6-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. The concentration of this compound needed to inhibit enzyme activity by 50% was 0.51 μM against the P. carinii enzyme, 0.09 μM against the T. gondii enzyme, and 0.35 μM against the rat enzyme. Thus, there was selectivity of binding to T. gondii enzyme, but not P. carinii enzyme, relative to rat enzyme. 2′,5′-Dimethoxybenzyl analogues were less active than the corresponding 3′,4′,5′-trimethoxybenzyl analogues, and compounds with a CH₂CH₂ or CH₂CH₂CH₂ bridge were less active than those with a CH₂ bridge. 2,4-Diamino-6-(2′-bromo-3′,4′,5′-trimethoxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine showed greater selectivity than trimetrexate or piritrexim for the P. carinii and T. gondii enzyme, but was less selective than trimethoprim or pyrimethamine. However its molar potency against both enzymes was greater than that of trimethoprim, the antifolate most commonly used, in combination with sulfamethoxazole, for initial treatment of opportunistic P. carinii and T. gondii infections in patients with AIDS and other disorders of the immune system.     

A simple, rapid and sensitive method for simultaneous determination of rivastigmine and its major metabolite NAP 226-90 in rat brain and plasma by reversed-phase liquid chromatography coupled to electrospray ionization mass spectrometry

A simple and sensitive reversed-phase liquid chromatography coupled with electrospray-mass spectrometry was developed and validated for the simultaneous determination of rivastigmine, a cholinesterase inhibitor, and its major metabolite NAP 226-90 in rat plasma and brain homogenates. Rivastigmine and NAP 226-90 were extracted from plasma and brain by ethyl acetate and, after drying under nitrogen, re-dissolved in acetonitrile and separated isocratic by HPLC on a C(18) column and quantified by single ion monitoring mass spectrometer. The mean (+/-SD) extraction efficiency for rivastigmine in plasma and brain was 93 +/- 2 and 95 +/- 2% (n = 5) of NAP 226-90 in a drug range of 10-100 pmol/mL or pmol/g. The method proved to be linear within the tested range (regression coefficient, r = 0.9999, n = 5). Intra- and inter-day precision coefficients of variation and accuracy bias were acceptable (within 15%, n = 5) over the entire range for both compounds using plasma or brain samples. The limits of quantification were 0.5 pmol/mL plasma and 2.5 pmol/g brain for rivastigmine and 1 pmol/mL plasma and 5 pmol/g brain for NAP 226-90, respectively. The analytical technique was used to determine the concentrations of rivastigmine and its metabolite NAP 226-90 in rat plasma and brain after oral drug administration. The concentrations of the parent drug and its major metabolite were compared to a pharmacodynamic parameter, the ex vivo inhibition of acetylcholinesterase.     

Multidimensional statistical analysis applied to electron ionization mass spectra to determine steroid stereochemistry

The differentiation of stereoisomers on the basis of their mass spectra only is usually a difficult challenge even when an informative ionization technique such as electron ionization is used; this is particularly the case for steroids. In this study, multivariate statistical techniques have been applied to the mass spectra of derivatized 5xi-androstane-3xi,17xi-diols (xi = alpha,beta) in order to investigate the possibility of discrimination among the different isomers. After collection of the data from the mass spectra (20 replicates for each of the 8 isomers), each ion was considered as a statistical variable and each mass spectrum as an observation. The more discriminative variables (42 out of the 160 initial ones) were selected using the analysis of variance technique (ANOVA). Thereafter, a linear discriminant analysis (LDA) allowed us to set up a predictive model for stereochemistry determination. The two-dimensional graphical display of the 160 observations on the basis of the canonical variables derived from LDA made it possible to separate the eight isomers. The discrimination of 5alpha and 5beta isomers as well as 3alpha and 3beta was unambiguous, whereas, the discrimination of 17alpha and 17beta epimers was less obvious. The robustness of the model was checked with 40 mass spectra recorded over a 6-month period on different quadrupole mass spectrometers and under different signal acquisition conditions. The percentage of correct assignment of these 'unknown' stereoisomers was 92%; only three 17alpha and 17beta epimers were not correctly plotted in the expected zone. Nevertheless, the performance score was better than those observed with traditional mass spectral libraries. Furthermore, this statistical approach allowed us to identify the main fragment ions involved in the discrimination between isomers: m/z 256 and 421 for isomers 5a-5b; m/z 241 and 331 for isomers 5alpha3alpha-5alpha3beta; m/z 143 and 162 for isomers 5beta3alpha-5beta3beta; and m/z 255 for epimers 17alpha-17beta.     

New multiresidue analytical method dedicated to trace level measurement of brominated flame retardants in human biological matrices

A new method has been developed for the multi-residue measurement of the main brominated flame retardants (alpha- and gamma-hexabromocyclododecane (HBCD), tetrabromobisphenol A (TBBP-A) and polybrominated diphenyl ethers including decabromodiphenyl ether) in human biological matrices (serum, adipose tissue and breast milk). The proposed sample preparation procedure focused on reduced solvent and consumable consumption and associated procedural contamination, as well as reduced sample size. This protocol was fully validated and was proved to be suitable for identification of brominated flame retardant residues at ultra-trace level, as attested by preliminary results on real samples.