Hollow-fiber liquid-phase microextraction of amphetamine-type stimulants in human hair samples

A fast method was optimized and validated in order to quantify amphetamine-type stimulants (amphetamine, AMP; methamphetamine, MAMP; fenproporex, FPX; 3,4-methylenedioxymethamphetamine, MDMA; and 3,4-methylenedioxyamphetamine, MDA) in human hair samples. The method was based in an initial procedure of decontamination of hair samples (50 mg) with dichloromethane, followed by alkaline hydrolysis and extraction of the amphetamines using hollow-fiber liquid-phase micro extraction (HF-LPME) in the three-phase mode. Gas chromatography-mass spectrometry (GC-MS) was used for identification and quantification of the analytes. The LoQs obtained for all amphetamines (around 0.05 ng/mg) were below the cut-off value (0.2 ng/mg) established by the Society of Hair Testing (SoHT). The method showed to be simple and precise. The intra-day and inter-day precisions were within 10.6% and 11.4%, respectively, with the use of only two deuteratecl internal standards (AMP-d5 and MDMA-d5). By using the weighted least squares linear regression (1/x(2)), the accuracy of the method was satisfied in the lower concentration levels (accuracy values better than 87%). Hair samples collected from six volunteers who reported regular use of amphetamines were submitted to the developed method. Drug detection was observed in all samples of the volunteers. (c) 2012 Elsevier B.V. All rights reserved.

A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers

Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. Objective: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). Methods: The study was an open-label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. Results: No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for t(max) and t(1/2) were 1.6 (+/- 0.4) h and 3.3 (+/- 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

Surgical treatment of globe subluxation in the active phase of the myogenic type of Graves orbitopathy: case reports

The purpose of the present article is to present and discuss two cases of globe subluxation in the active phase of myogenic Graves' orbitopathy and to evaluate the prevalence of this phenomenon. Two patients with the myogenic variant of Graves' orbitopathy that had being treated with oral and intravenous steroid pulses developed globe subluxation. Both had to have urgent eyelid and orbital decompression. After these observations, we reviewed the medical records of a sample of 284 patients (482 orbits) who had had orbital decompression at our Institution from 1992 to 2010, with a search for cases presenting severe proptosis or globe subluxation in the active phase of myogenic Graves' orbitopathy. No patient had to have decompression for globe subluxation in the active phase of Graves' orbitopathy. The prevalence of this event as an indication for surgery in the myogenic variant of Graves' orbitopathy was therefore 0.7% (2/284) or even less. The combination of lowering the upper eyelid and orbital decompression had a dramatic therapeutic effect on these patients despite the presence of intense inflammatory signs in the orbits. In conclusion, patients affected with the myogenic variant of Graves' orbitopathy may develop globe subluxation. Urgent surgical treatments should not be postponed despite the presence of active inflammation.

An Asymmetric Extension for the Family of Elliptical Slash Distributions

In this article, we introduce an asymmetric extension to the univariate slash-elliptical family of distributions studied in Gomez et al. (2007a). This new family results from a scale mixture between the epsilon-skew-symmetric family of distributions and the uniform distribution. A general expression is presented for the density with special cases such as the normal, Cauchy, Student-t, and Pearson type II distributions. Some special properties and moments are also investigated. Results of two real data sets applications are also reported, illustrating the fact that the family introduced can be useful in practice.

Gas-phase reactivity of protonated 2-oxazoline derivatives: mass spectrometry and computational studies

RATIONALE: Oxazolines have attracted the attention of researchers worldwide due to their versatility as carboxylic acid protecting groups, chiral auxiliaries, and ligands for asymmetric catalysis. Electrospray ionization tandem mass spectrometric (ESI-MS/MS) analysis of five 2-oxazoline derivatives has been conducted, in order to understand the influence of the side chain on the gas-phase dissociation of these protonated compounds under collision-induced dissociation (CID) conditions. METHODS: Mass spectrometric analyses were conducted in a quadrupole time-of-flight (Q-TOF) spectrometer fitted with electrospray ionization source. Protonation sites have been proposed on the basis of the gas-phase basicity, proton affinity, atomic charges, and a molecular electrostatic potential map obtained on the basis of the quantum chemistry calculations at the B3LYP/6-31 + G(d, p) and G2(MP2) levels. RESULTS: Analysis of the atomic charges, gas-phase basicity and proton affinities values indicates that the nitrogen atom is a possible proton acceptor site. On the basis of these results, two main fragmentation processes have been suggested: one taking place via neutral elimination of the oxazoline moiety (99 u) and another occurring by sequential elimination of neutral fragments with 72 u and 27 u. These processes should lead to formation of R+. CONCLUSIONS: The ESI-MS/MS experiments have shown that the side chain could affect the dissociation mechanism of protonated 2-oxazoline derivatives. For the compound that exhibits a hydroxyl at the lateral chain, water loss has been suggested to happen through an E2-type elimination, in an exothermic step. Copyright (C) 2012 John Wiley & Sons, Ltd.

Estimation and diagnostics for heteroscedastic nonlinear regression models based on scale mixtures of skew-normal distributions

An extension of some standard likelihood based procedures to heteroscedastic nonlinear regression models under scale mixtures of skew-normal (SMSN) distributions is developed. This novel class of models provides a useful generalization of the heteroscedastic symmetrical nonlinear regression models (Cysneiros et al., 2010), since the random term distributions cover both symmetric as well as asymmetric and heavy-tailed distributions such as skew-t, skew-slash, skew-contaminated normal, among others. A simple EM-type algorithm for iteratively computing maximum likelihood estimates of the parameters is presented and the observed information matrix is derived analytically. In order to examine the performance of the proposed methods, some simulation studies are presented to show the robust aspect of this flexible class against outlying and influential observations and that the maximum likelihood estimates based on the EM-type algorithm do provide good asymptotic properties. Furthermore, local influence measures and the one-step approximations of the estimates in the case-deletion model are obtained. Finally, an illustration of the methodology is given considering a data set previously analyzed under the homoscedastic skew-t nonlinear regression model. (C) 2012 Elsevier B.V. All rights reserved.

The involvement of the spleen during chronic phase of Schistosoma mansoni infection in galectin-3(-/-) mice

Schistosoma mansoni synthesizes glycoconjugates which interact with galectin-3, eliciting an intense humoral immune response. Moreover, it was demonstrated that galectin-3 regulates B cell differentiation into plasma cells. Splenomegaly is a hallmark event characterized by polyclonal B cell activation and enhancement of antibody production. Here, we investigated whether galectin-3 interferes with spleen organization and B cell compartment during chronic schistosomiasis, using wild type (WT) and galectin-3(-/-) mice. In chronically-infected galectin-3(-/-) mice the histological architecture of the spleen, including white and red pulps, was disturbed with heterogeneous lymphoid follicles, an increased number of plasma cells (CD19(-)B220(-/low)CD138(+)) and a reduced number of macrophages (CD19(-)B220(-)Mac-1(+)CD138(-)) and B lymphocytes (CD19(+)B220(+/high)CD138(-)), compared with the WT infected mice. In the absence of galectin-3 there was an increase of annexin-V+PI- cells and a major presence of apoptotic cells in spleen compared with WT infected mice. In spleen of WT infected mice galectin-3 was largely expressed in lymphoid follicles and extrafollicular sites. Thus, we propose that galectin-3 plays a role in splenic architecture, controlling distinct events such as apoptosis, macrophage activity, B cell differentiation and plasmacytogenesis in the course of S. mansoni infection.

Overall Survival Improvement in Patients with Lung Cancer and Bone Metastases Treated with Denosumab Versus Zoledronic Acid Subgroup Analysis from a Randomized Phase 3 Study

Introduction: Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Methods: Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Results: Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. Conclusion: In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

Rounding of a first-order quantum phase transition to a strong-coupling critical point

We investigate the effects of quenched disorder on first-order quantum phase transitions on the example of the N-color quantum Ashkin-Teller model. By means of a strong-disorder renormalization group, we demonstrate that quenched disorder rounds the first-order quantum phase transition to a continuous one for both weak and strong coupling between the colors. In the strong-coupling case, we find a distinct type of infinite-randomness critical point characterized by additional internal degrees of freedom. We investigate its critical properties in detail and find stronger thermodynamic singularities than in the random transverse field Ising chain. We also discuss the implications for higher spatial dimensions as well as unusual aspects of our renormalization-group scheme. DOI: 10.1103/PhysRevB.86.214204

Actions of the Kunitz-type serine protease inhibitor Amblyomin-X on VEGF-A-induced angiogenesis

Amblyomin-X is a Kunitz-type serine protease inhibitor (Kunitz-type SPI) designed from the cDNA library of the Amblyomma cajennense tick, which displays in vivo anti-tumor activities. Here, the mechanisms of actions of Amblyomin-X in vascular endothelial growth factor A (VEGF-A)-induced angiogenesis were characterized. Topical application of Amblyomin-X (10 or 100 ng/10 mu l; each 48 h) inhibited VEGF-A-induced (10 ng/10 mu l; each 48 h) angiogenesis in the dorsal subcutaneous tissue in male Swiss mice. Moreover, similar effect was observed in the VEGF-A-induced angiogenesis in the chicken chorioallantoic membrane (CAM). Additional in vitro assays in t-End cells showed that Amblyomin-X treatment delayed the cell cycle, by maintaining them in G0/G1 phase, and inhibited cell proliferation and adhesion, tube formation and membrane expression of the adhesion molecule platelet-endothelial cell adhesion molecule-1 (PECAM-I), regardless of mRNA synthesis. Together, results herein reveal the role of Kunitz-type SPI on in vivo VEGF-A-induced angiogenesis, by exerting modulatory actions on endothelial cell proliferation and adhesion, especially on membrane expression of PECAM-1. These data provide further mechanisms of actions of Kunitz-type SPI, corroborating their relevance as scientific tools in the design of therapeutic molecules. (C) 2012 Elsevier Ltd. All rights reserved.

Characterization of multiple reflections and phase space properties for a periodically corrugated waveguide

Dynamical properties for a beam light inside a sinusoidally corrugated waveguide are discussed in this paper. The beam is confined inside two-mirrors: one is flat and the other one is sinusoidally corrugated. The evolution of the system is described by the use of a two-dimensional and nonlinear mapping. The phase space of the system is of mixed type therefore exhibiting a large chaotic sea, periodic islands and invariant KAM curves. A careful discussion of the numerical method to solve the transcendental equations of the mapping is given. We characterize the probability of observing successive reflections of the light by the corrugated mirror and show that it is scaling invariant with respect to the amplitude of the corrugation. Average properties of the chaotic sea are also described by the use of scaling arguments.

Corrole isomers: intrinsic gas-phase shapes via traveling wave ion mobility mass spectrometry and dissociation chemistries via tandem mass spectrometry

Corrole and four of its isomers with subtle structural changes promoted by exchange of nitrogen and carbon atoms in the corrole ring have been studied by traveling wave ion mobility mass spectrometry and collision induced dissociation experiments. Significant differences in shapes and charge distributions for their protonated molecules were found to lead to contrasting gas phase mobilities, most particularly for corrorin, the most "confused" isomer. Accordingly, corrorin was predicted by B3LYP/6-31g(d,p) and collisional cross section calculations to display the most compact tri-dimensional structure, whereas NCC4 and corrole were found to be the most planar isomers. Better resolution between the corrole isomers was achieved using the more polarizable and massive CO2 as the drift gas. Sequential losses of HF molecules were found to dominate the dissociation chemistry of the protonated molecules of these corrole isomers, but their unique structures caused contrasting labilities towards CID, whereas NCC4 showed a peculiar and structurally diagnostic loss of NH3, allowing its prompt differentiation from the other isomers.

Development of a slow-wave MEMS phase shifter on CMOS technology for millimeter wave frequencies

We propose a slow-wave MEMS phase shifter that can be fabricated using the CMOS back-end and an additional maskless post-process etch. The tunable phase shifter concept is formed by a conventional slow-wave transmission line. The metallic ribbons that form the patterned floating shield of this type of structure are released to allow motion when a control voltage is applied, which changes the characteristic impedance and the phase velocity. For this device a quality factor greater than 40 can be maintained, resulting in a figure of merit on the order of 0.7 dB/360 degrees and a total area smaller than 0.14 mm(2) for a 60-GHz working frequency. (C) 2011 Elsevier B.V. All rights reserved.

Effect of the Type of Emulsifying Salt on Microstructure and Rheological Properties of "Requeijao Cremoso" Processed Cheese Spreads

The role of different types of emulsifying saltssodium citrate (TSC), sodium hexametaphosphate (SHMP), sodium tripolyphosphate (STPP) and tetrasodium pyrophosphate (TSPP)on microstructure and rheology of requeijao cremoso processed cheese was determined. The cheeses manufactured with TSC, TSPP, and STPP behaved like concentrated solutions, while the cheese manufactured with SHMP exhibited weak gel behavior and the lowest values for the phase angle (G/G). This means that SHMP cheese had the protein network with the largest amount of molecular interactions, which can be explained by its highest degree of fat emulsification. Rotational viscometry indicated that all the spreadable cheeses behaved like pseudoplastic fluids. The cheeses made with SHMP and TSPP presented low values for the flow behavior index, meaning that viscosity was more dependent on shear rate. Regarding the consistency index, TSPP cheese showed the highest value, which could be attributed to the combined effect of its high pH and homogeneous fat particle size distribution.

Fractionation of lemon essential oil by solvent extraction: Phase equilibrium for model systems at T=298.2 K

The fractioning of lemon essential oil can be performed by liquid-liquid extraction using hydrous ethanol as a solvent. A quaternary mixture composed of limonene, gamma-terpinene, beta-pinene, and citral was used to simulate lemon essential oil. In this paper, we present (liquid + liquid) equilibrium data that were experimentally determined for systems containing essential oil compounds, ethanol, and water at T = 298.2 K. The experimental data were correlated using the NRTL and UNIQUAC models, and the mean deviations between calculated and experimental data were less than 0.0053 in all systems, indicating the accuracy of these molecular models in describing our systems. The results show that as the water content in the solvent phase increased, the values of the distribution coefficients decreased, regardless of the type of compound studied. However, the oxygenated compound always showed the highest distribution coefficient among the components of the essential oil, thus making deterpenation of the lemon essential oil a feasible process. (C) 2012 Elsevier Ltd. All rights reserved.