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We report the first measurements of the moments--mean (M), variance (σ(2)), skewness (S), and kurtosis (κ)--of the net-charge multiplicity distributions at midrapidity in Au+Au collisions at seven energies, ranging from sqrt[sNN]=7.7 to 200 GeV, as a part of the Beam Energy Scan program at RHIC. The moments are related to the thermodynamic susceptibilities of net charge, and are sensitive to the location of the QCD critical point. We compare the products of the moments, σ(2)/M, Sσ, and κσ(2), with the expectations from Poisson and negative binomial distributions (NBDs). The Sσ values deviate from the Poisson baseline and are close to the NBD baseline, while the κσ(2) values tend to lie between the two. Within the present uncertainties, our data do not show nonmonotonic behavior as a function of collision energy. These measurements provide a valuable tool to extract the freeze-out parameters in heavy-ion collisions by comparing with theoretical models.

We report the STAR measurements of dielectron (e(+)e(-)) production at midrapidity (|y(ee)|<1) in Au+Au collisions at √[s(NN)]=200  GeV. The measurements are evaluated in different invariant mass regions with a focus on 0.30-0.76 (ρ-like), 0.76-0.80 (ω-like), and 0.98-1.05 (ϕ-like)   GeV/c(2). The spectrum in the ω-like and ϕ-like regions can be well described by the hadronic cocktail simulation. In the ρ-like region, however, the vacuum ρ spectral function cannot describe the shape of the dielectron excess. In this range, an enhancement of 1.77±0.11(stat)±0.24(syst)±0.33(cocktail) is determined with respect to the hadronic cocktail simulation that excludes the ρ meson. The excess yield in the ρ-like region increases with the number of collision participants faster than the ω and ϕ yields. Theoretical models with broadened ρ contributions through interactions with constituents in the hot QCD medium provide a consistent description of the dilepton mass spectra for the measurement presented here and the earlier data at the Super Proton Synchrotron energies.

Different chemotypes are described as anti-inflammatory. Among them the N-acylhydrazones (NAH) are highlighted by their privileged structure nature, being present in several anti-inflammatory drug-candidates. In this paper a series of functionalized 3-aminothiophene-2-acylhydrazone derivatives 5a-i were designed, synthesized and bioassayed. These new derivatives showed great anti-inflammatory and analgesic potency and efficacy. Compounds 5a and 5d stand out in this respect, and were also active in CFA-induced arthritis in rats. After daily treatment for seven days with 5a and 5d (50 µmol/Kg), by oral administration, these compounds were not renal or hepatotoxic nor immunosuppressive. Compounds 5a and 5d also displayed good drug-scores and low risk toxicity calculated in silico using the program OSIRIS Property Explorer.

Background: This study evaluated in vivo the accuracy of metal (Smart®) and plastic (Triple Tray®) dual-arch trays used with vinyl polysiloxane (Flexitime®), in the putty/wash viscosity, as well as polyether (Impregum Soft®) in the regular viscosity., Materials and Methods: In one patient, an implant-level transfer was screwed on an implant in the mandibular right first molar, serving as a pattern. Ten impressions were made with each tray and impression material. The impressions were poured with Type IV gypsum. The width and height of the pattern and casts were measured in a profile projector (Nikon). The results were submitted to Student's t-test for one sample (α = 0.05)., Results: For the width distance, the plastic dual-arch trays with vinyl polysiloxane (4.513 mm) and with polyether (4.531 mm) were statistically wider than the pattern (4.489 mm). The metal dual-arch tray with vinyl polysiloxane (4.504 mm) and with polyether (4.500 mm) did not differ statistically from the pattern. For the height distance, only the metal dual-arch tray with polyether (2.253 mm) differed statistically from the pattern (2.310 mm)., Conclusion: The metal dual-arch tray with vinyl polysiloxane, in the putty/wash viscosities, reproduced casts with less distortion in comparison with the same technique with the plastic dual-arch tray. The plastic or metal dual-arch trays with polyether reproduced cast with greater distortion. How to cite the article: Santayana de Lima LM, Borges GA, Burnett LH Jr, Spohr AM. In vivo study of the accuracy of dual-arch impressions. J Int Oral Health 2014;6(3):50-5.

The synthesis of a new cross-bridged 1,4,8,11-tetraazacyclotetradecane (cb-cyclam) derivative bearing a picolinate arm (Hcb-te1pa) was achieved by taking advantage of the proton sponge properties of the starting constrained macrocycle. The structure of the reinforced ligand as well as its acid-base properties and coordination properties with Cu(2+) and Zn(2+) was investigated. The X-ray structure of the free ligand showed a completely preorganized conformation that lead to very fast copper(II) complexation under mild conditions (instantaneous at pH 7.4) or even in acidic pH (3 min at pH 5) at room temperature and that demonstrated high thermodynamic stability, which was measured by potentiometry (at 25 °C and 0.10 M in KNO3). The results also revealed that the complex exists as a monopositive copper(II) species in the intermediate pH range. A comparative study highlighted the important selectivity for Cu(2+) over Zn(2+). The copper(II) complex was synthesized and investigated in solution using different spectroscopic techniques and DFT calculations. The kinetic inertness of the copper(II) complex in acidic medium was evaluated by spectrophotometry, revealing the very slow dissociation of the complex. The half-life of 96 days, in 5 M HClO4, and 465 min, in 5 M HCl at 25 °C, show the high kinetic stability of the copper(II) chelate compared to that of the corresponding complexes of other macrocyclic ligands. Additionally, cyclic voltammetry experiments underlined the perfect electrochemical inertness of the complex as well as the quasi-reversible Cu(2+)/Cu(+) redox system. The coordination geometry of the copper center in the complex was established in aqueous solution from UV-vis and EPR spectroscopies.

Two cyclen (1,4,7,10-tetraazacyclododecane) derivatives bearing trans-bis(2-hydroxybenzyl) arms, the 1,7-(2-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (H2do2ph) and its cross-bridged counterpart (H2cb-do2ph), have been synthesized, aiming toward the possible use of their copper(II) and gallium(III) complexes in nuclear medicine. The protonation of both compounds was studied in aqueous solution as well as their complexes with Cu(2+) and Ga(3+) cations. The complexes of both ligands with Ca(2+) and Zn(2+) metal ions were also studied due to the abundance of these cations in biological media. In mild conditions the complexes of Ca(2+) and Ga(3+) with H2cb-do2ph did not form. The behavior of the two ligands and their complexes was compared by the values of the equilibrium constants, the data of varied spectroscopic techniques, the values of redox potentials of their copper(II) complexes, and the resistance of the complexes to acid dissociation. It was expected that, as found for related pairs of cyclen and cyclam (1,4,8,11-tetraazacyclotetradecane) derivatives, the cross-bridged macrocyclic derivative could be an excellent ligand for the complexation of copper(II). Additionally, the N-2-hydroxybenzyl groups were chosen due to their known ability to coordinate the gallium(III) cation. Due to the small size of the latter cation and its particular propensity to form hexacoordinate complexes, it was also expected that there would be a good ability of both ligands for the uptake of Ga(3+). Surprisingly, the results revealed that the cyclen derivative H2do2ph is the best ligand for the coordination of Cu(2+) and Ga(3+) cations, not only from their thermodynamic stability as expected but also from their kinetic inertness, when compared with its cross-bridged counterpart.

Background: Pulmonary arterial hypertension (PAH) is a disease that results in right ventricular (RV) dysfunction. While pulmonary vascular disease is the primary pathological focus, RV hypertrophy and RV dysfunction are the major determinants of prognosis in PAH. The aim of this study was to investigate the effects of (E)-N'-(3,4-dimethoxybenzylidene)-4-methoxybenzohydrazide (LASSBio-1386), an N-acylhydrazone derivative, on the lung vasculature and RV dysfunction induced by experimental PAH., Methods: Male Wistar rats were injected with a single dose (60mg/kg, i.p.) of monocrotaline (MCT) and given LASSBio-1386 (50mg/kg, p.o.) or vehicle for 14 days. The hemodynamic, exercise capacity (EC), endothelial nitric oxide synthase (eNOS), adenosine A2A receptor (A2AR), sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a), phospholamban (PLB) expression, Ca(2+)-ATPase activity and vascular activity of LASSBio-1386 were evaluated., Results and Conclusions: The RV systolic pressure was elevated in the PAH model and reduced from 49.6 ± 5.0 mm Hg (MCT group) to 27.2 ± 2.1 mm Hg (MCT+LASSBio-1386 group; P<0.05). MCT administration also impaired the EC, increased the RV and pulmonary arteriole size, and promoted endothelial dysfunction of the pulmonary artery rings. In the PAH group, the eNOS, A2AR, SERCA2a, and PLB levels were changed compared with the control; in addition, the Ca(2+)-ATPase activity was reduced. These alterations were related with MCT-injected rats, and LASSBio-1386 had favorable effects that prevented the development of PAH. LASSBio-1386 is effective at preventing endothelial and RV dysfunction in PAH, a finding that may have important implications for ongoing clinical evaluation of A2AR agonists for the treatment of PAH., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e.g., Vinca alkaloids) and microtubule-stabilizing (e.g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on β-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM and ≥4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.

We report the beam energy (sqrt[sNN]=7.7-200  GeV) and collision centrality dependence of the mean (M), standard deviation (σ), skewness (S), and kurtosis (κ) of the net-proton multiplicity distributions in Au+Au collisions. The measurements are carried out by the STAR experiment at midrapidity (|y|<0.5) and within the transverse momentum range 0.4

Novel 2-chloro-4-anilino-quinazolines designed as EGFR and VEGFR-2 dual inhibitors were synthesized and evaluated for inhibitory effects. EGFR and VEGFR-2 are validated targets in cancer therapy and combined inhibition might be synergistic for both antitumor activity and resistance prevention. The biological data obtained proved the potential of 2-chloro-4-anilino-quinazoline derivatives as EGFR and VEGFR-2 dual inhibitors, highlighting compound 8o, which was approximately 7-fold more potent on VEGFR-2 and approximately 11-fold more potent on EGFR compared to the prototype 7. SAR and docking studies allowed the identification of pharmacophoric groups for both kinases and demonstrated the importance of a hydrogen bond donor at the para position of the aniline moiety for interaction with conserved Glu and Asp amino acids in EGFR and VEGFR-2 binding sites., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

With current advances in genomics, several technological processes have been generated, resulting in improvement in different segments of molecular research involving prokaryotic and eukaryotic systems. A widely used contribution is the identification of new genes and their functions, which has led to the elucidation of several issues concerning cell regulation and interactions. For this, increase in the knowledge generated from the identification of promoters becomes considerably relevant, especially considering that to generate new technological processes, such as genetically modified organisms, the availability of promoters that regulate the expression of new genes is still limited. Considering that this issue is essential for biotechnologists, this paper presents an updated review of promoters, from their structure to expression, and focuses on the knowledge already available in eukaryotic systems. Information on current promoters and methodologies available for studying their expression are also reported.

In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl- LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4-dimethoxyphenyl and 1,3- benzodioxole subunits, respectively, in agreement with the in silico prediction using MetaSite Program. The development of a reproducible analytical methodology for the major metabolites by using HPLC-MS showed that both reactions require NADPH generating system and appeared to be catalyzed by cytochrome P450 (CYP). The identification of which isoenzyme was involved in the oxidative metabolism of LASSBio-448 was carried out by pre-incubations with the selective inhibitors sulfaphenazole (CYP2C9), quinidine (CYP2D6), furafylline (CYP1A2), p-nitrophenol (CYP2E1), ticlopidine (CYP2C19) and ketoconazole (CYP3A4). CYP1A2, CYP2C19 and CYP3A4 were demonstrated to be involved in the oxidative biotransformation of LASSBio-448.

Lipases are triacyl glycerol acyl hydrolases, which catalyze hydrolysis of esters, esterification and transesterification reactions, among others. Some of these enzymes have a large hydrophobic pocket covered by an alpha-helical mobile surface loop (the lid). Protein-protein interactions can occur through adsorption of two open lids of individual lipases. We investigated the conformation and oligomeric state of Thermomyces lanuginosus lipase (TLL) in solution by spectroscopic and mass spectrometry techniques. Information about oligomerization of this important industrial enzyme is only available for TLL crystals; therefore, we have done a throughout investigation of the conformation of this lipase in solution. SDS-PAGE and mass spectrometry analysis of size-exclusion chromatography eluted fractions indicated the presence of both monomeric and dimeric populations of TLL. The stability of the enzyme upon thermal and guanidine hydrochloride treatment was examined by circular dichroism and fluorescence emission spectroscopy. Small angle x-ray scattering and ion mobility mass spectrometry analysis revealed that TLL is found as a mixture of monomers and dimers at the assayed concentrations. Although previous x-ray diffraction data showed TLL as a dimer in the crystal (PDB: 1DT3), to our knowledge our report is the first evidencing that TLL co-exists as stable dimeric and monomeric forms in solution., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We have studied regular acting, wild-type human insulin at potency of 100 U/mL from four different pharmaceutical products directly from their final finished formulation by the combined use of mass spectrometry (MS), dynamic light scattering (DLS), small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR), and single-crystal protein crystallography (PX). All products showed similar oligomeric assembly in solution as judged by DLS and SAXS measurements. The NMR spectra were compatible with well folded proteins, showing close conformational identity for the human insulin in the four products. Crystallographic assays conducted with the final formulated products resulted in all insulin crystals belonging to the R3 space group with two a dimer in the asymmetric unit, both with the B-chain in the T configuration. Meta-analysis of the 24 crystal structures solved from the four distinct insulin products revealed close similarity between them regardless of variables such as biological origin, product batch, country origin of the product, and analytical approach, revealing a low conformational variability for the converging insulin structural ensemble. We propose the use of MS, SAXS, NMR fingerprint, and PX as a precise chemical and structural proof of folding identity of regular insulin in the final, formulated product., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We modified amylin chemically by conjugating methoxyl polyethyleneglycol succinimidyl carbonate (mPEGSC) of varying molecular weights (1 kDa, 2 kDa and 5 kDa). The reaction occurred within a few minutes, resulting in at least four distinct PEGylated products. The reaction products were separated by reversed-phase chromatography and identified by mass-spectrometry. The monoPEGylated and diPEGylated amylin products were generated rapidly through conjugation to the two amino groups of the N-terminal lysine residue. Both PEGylated amylin products bound to the receptor activity-modifying protein 1 (RAMP1). Pharmacological evaluation by subcutaneous administration in mice of monoPEGylated and diPEGylated amylin obtained with mPEG-SC 5 kDa revealed that both compounds modulated glycemia for longer times than unmodified amylin. Collectively, these data demonstrate the potential of bioconjugation with mPEG for the design of amylin therapeutics with sustained action.

Amylin is a pancreatic hormone co-secreted with insulin. Human amylin has been shown to form dimers and exhibit high propensity for amyloid fibril formation. We observed the ability of the water-soluble murine amylin to aggregate in water resulting in an insoluble material with Thioflavin T binding properties. Infrared spectroscopy analysis revealed beta-sheet components in the aggregated murine amylin. Morphological analysis by transmission electron microscopy and atomic force microscopy provided access to the fibril nature of the murine amylin aggregate which is similar to amyloid fibrils from human amylin. X-ray diffraction of the murine amylin fibrils showed peaks at 4.7Å and 10Å, a fingerprint for amyloid fibrils. Electron spray ionization-ion mobility spectroscopy-mass spectrometry (ESI-IMS-MS) analysis and crosslinking assays revealed self-association intermediates of murine amylin into high order oligomeric assemblies. These data demonstrate the stepwise association mechanism of murine amylin into stable oligomers, which ultimately converges to its organization into amyloid fibrils., (© 2013.)

Amylin is a pancreatic hormone that plays important roles in overall metabolism and in glucose homeostasis. The therapeutic restoration of postprandial and basal amylin levels is highly desirable for patients with diabetes who need to avoid glucose excursions. Protein conjugation with polyethylene glycol (PEG) has long been known to be a convenient approach for extending the biological effects of biopharmaceuticals. We have investigated the reactivity of amylin with methoxy polyethylene glycol succinimidyl carbonate and methoxy polyethylene glycol succinimidyl propionate, which have an average molecular weight of 5 kDa. The reaction, which was conducted in both aqueous and organic (dimethyl sulfoxide) solvents, occurred within a few minutes and resulted in at least four detectable products with distinct kinetic phases. These results suggest a kinetic selectivity for PEGylation by succinimidyl derivatives; these derivatives exhibit enhanced reactivity with primary amine groups, as indicated by an evaluation of the remaining amino groups using fluorescamine. The analysis of tryptic fragments from mono- and diPEGylated amylin revealed that conjugation occurred within the 1-11 amino acid region, most likely at the two amine groups of Lys(1). The reaction products were efficiently separated by C-18 reversed phase chromatography. Binding assays confirmed the ability of mono- and diPEGylated amylin to interact with the amylin co-receptor receptor activity-modifying protein 2. Subcutaneous administration in mice revealed the effectiveness of monoPEG-amylin and diPEG-amylin in reducing glycemia; both compounds exhibited prolonged action compared to unmodified amylin. These features suggest the potential use of PEGylated amylin to restore basal amylin levels.

The measurement of J/ψ azimuthal anisotropy is presented as a function of transverse momentum for different centralities in Au+Au collisions at sqrt[s(NN)]=200 GeV. The measured J/ψ elliptic flow is consistent with zero within errors for transverse momentum between 2 and 10 GeV/c. Our measurement suggests that J/ψ particles with relatively large transverse momenta are not dominantly produced by coalescence from thermalized charm quarks, when comparing to model calculations.

Lipoprotein-A (LpA) is an emerging independent risk factor for cerebro- and cardio-vascular diseases (CCVD). Recognizing its function and its normal distribution is of fundamental importance for a better understanding of CCVD patho-physiology. The present study evaluated plasma LpA levels of healthy university students using turbidimetric methods. Medians and inter-quartile differences obtained for male and female participants were 11.3mg/dL (3.1-30.7) and 20.9mg/dL (6.5-42.3), respectively, demonstrating a significant difference (P=0.017) between men and women. A third of students showed plasma concentrations above reference values. Our results indicate that 33% of students possess a hidden independent risk factor for CCVD. Multi-disciplinary evaluation and characterization of young individuals should be recommended in an attempt to take early preventive measures and to eliminate possible modifiable risk factors such as sedentary lifestyle, smoking, hypertension, obesity and atherogenic diet., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The addition of surfactants to lipid bilayers is important for the modulation of lipid bilayer properties (e.g., in protein reconstitution and development of nonviral gene delivery vehicles) and to provide insight on the properties of natural biomembranes. In this work, the thermal behavior, organization, and nanomechanical stability of model cationic lipid-surfactant bilayers have been investigated. Two different cationic surfactants, hexadecyltrimethylammonium bromide (CTAB) and a novel derivative of the amino acid serine (Ser16TFAc), have been added (up to 50 mol %) to both liposomes and supported lipid bilayers (SLBs) composed by the zwitterionic phospholipid DPPC. The thermal phase behavior of mixed liposomes has been probed by differential scanning calorimetry (DSC), and the morphology and nanomechanical properties of mixed SLBs by atomic force microscopy-based force spectroscopy (AFM-FS). Although DSC thermograms show different results for the two mixed liposomes, when both are deposited on mica substrates similar trends on the morphology and the mechanical response of the lipid-surfactant bilayers are observed. DSC thermograms indicate microdomain formation in both systems, but while CTAB decreases the degree of organization on the liposome bilayer, Ser16TFAc ultimately induces the opposite effect. Regarding the AFM-FS studies, they show that microphase segregation occurs for these systems and that the effect is dependent on the surfactant content. In both SLB systems, different microdomains characterized by their height and breakthrough force Fb are formed. The molecular organization and composition is critically discussed in the light of our experimental results and literature data on similar lipid-surfactant systems.

Falcipain-2 is a cysteine protease of the malaria parasite Plasmodium falciparum that plays a key role in the hydrolysis of hemoglobin, a process that is required by intraerythrocytic parasites to obtain amino acids. In this work we show that the polysulfonated napthylurea suramin is capable of binding to falcipain-2, inhibiting its catalytic activity at nanomolar concentrations against both synthetic substrates and the natural substrate hemoglobin. Kinetic measurements suggest that the inhibition occurs through an noncompetitive allosteric mechanism, eliciting substrate inhibition. Smaller suramin analogues and those with substituted methyl groups also showed inhibition within the nanomolar range. Our results identify the suramin family as a potential starting point for the design of falcipain-2 inhibitor antimalarials that act through a novel inhibition mechanism., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The aim of this study is to evaluate the investigation actions of home contacts of tuberculosis (TB) index cases in the Tuberculosis Control Program (TCP) of Pelotas/RS - Brazil. This cross-sectional descriptive study was based on data from the records of index cases. The sample consisted of 163 contacts of 68 subjects with pulmonary TB in treatment in the TCP between June and August, 2009. These contacts were predominantly female, over 10 years of age and the daughters of index cases. The requested examination was a chest radiography and bacilloscopy. Active TB was found in 1.8 % of contacts. Results show that assistance for TB patients in Pelotas-Brazil, which is centralized in a single specialized service, hinders the investigation of home contacts. Primary care is required to narrow the gap between professionals and the family, and facilitate early diagnosis and interruption of the TB transmission chain in a timely manner.

Two new cyclen derivatives, H(2)do2nph and H(2)cb-do2nph, containing two trans-2-methyl-4-nitrophenol pendant arms and the latter including also an ethylene cross-bridge, were prepared in good yields using the bisaminal synthetic route. The two ligands were studied comparatively regarding their metal complexation behaviour. The copper(II) and zinc(II) complexes of H(2)do2nph and H(2)cb-do2nph were studied in dimethylsulfoxide-water (9 : 1 v/v) solution by a range of spectroscopic techniques. Copper(II) complexes were also studied in solid state by X-ray single crystal diffraction. These studies showed that the copper(II) and zinc(II) complexes of H(2)do2nph exhibited a distorted square pyramidal coordination environment with the four nitrogen atoms of the cyclen ring defining the basal plane, and that one of the nitrophenolate arms did not coordinate to the metal, independently of its protonation state. On the other hand, depending on the protonation state of one of the nitrophenolic arms, the cross-bridged derivative forms copper(II) complexes with distorted square pyramidal or octahedral geometries with one or two arms coordinated to the metal centre, respectively. In the complex with distorted octahedral geometry, the two phenolic oxygen atoms are coordinated to the metal centre in a cis-fashion. Acid-assisted dissociation assays in 1 mol dm(-3) HCl DMSO-H(2)O (9 : 1 v/v) solution at 298.2 K allowed one to determine the half-life of both copper(II) complexes, which is lower for the derivative without a cross-bridge as expected, while for the other one it is quite high and in line with similar cross-bridged cyclen derivatives from the literature.

The synthesis and characterization of Hno1pa2py, a new tacn-based ligand, is reported. The complexation process with Cu(2+) was proved to be very fast even in acidic medium. Potentiometric titrations allowed us to establish that Hno1pa2py exhibits an overall low basicity as well as a high selectivity for Cu(2+) over Zn(2+) cations. The copper(II) complex was synthesized and characterized using UV-vis and EPR spectroscopies and density functional theory (DFT) calculations. The studies clearly showed that the [Cu(no1pa2py)](+) complex is present in solution as a mixture of two isomers in which the ligand is coordinated to the metal center using a N5O donor set with the metal center in a distorted octahedral geometry. The very high kinetic inertness of the [Cu(no1pa2py)](+) complex was demonstrated by using acid-assisted dissociation assays as well as cyclic voltammetry. Preliminary investigations of (64)Cu complexation were performed to validate the potential use of such chelating agent for further application in nuclear medicine. The X-ray crystal structures of copper(II) complexes of L1, the ester derivative of Hno1pa2py, have been determined.

Purpose: To investigate the impact of pregnancy on female sexual function., Methods: An analytical, cross-sectional study was conducted on 181 non-pregnant and 177 pregnant women aged 18 to 45 years. The study included premenopausal, sexually active women with a steady partner and excluded those taking antidepressants or with a diagnosis of depression. Eleven of these women (6.2%) were in the first trimester, 50 (28.2%), in the second trimester and 116 (65.5%), in the third trimester of pregnancy. The evaluation consisted of an interview in which the Female Sexual Function Index (FSFI) was applied. The data were analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 16.0. The nonparametric Mann-Whitney test was used to compare the mean FSFI values of pregnant and non-pregnant women., Results: Sexual dysfunction was 40.4% among pregnant women and 23.3% among non-pregnant women, with a significant difference between the scores of the studied groups (p=0.01). The difference in the mean global FSFI values between the groups was also significant (p<0.0001). There were significant differences between pregnant and non-pregnant women regarding desire (p<0.0001), excitation (p=0.003), lubrication (p=0.02), orgasm (p=0.005) and satisfaction (p=0.03). The same was not observed regarding pain., Conclusion: We conclude that pregnancy negatively influences female sexual function, particularly the desire and excitement domains, revealing the importance of addressing the issue by professionals dealing with pregnant women.

Elliptic flow (v(2)) values for identified particles at midrapidity in Au + Au collisions, measured by the STAR experiment in the beam energy scan at RHIC at sqrt[s(NN)] = 7.7-62.4 GeV, are presented. A beam-energy-dependent difference of the values of v(2) between particles and corresponding antiparticles was observed. The difference increases with decreasing beam energy and is larger for baryons compared to mesons. This implies that, at lower energies, particles and antiparticles are not consistent with the universal number-of-constituent-quark scaling of v(2) that was observed at sqrt[s(NN)] = 200 GeV.

In bacteria selenocysteyl-tRNA(sec) (SelC) is synthesized by selenocysteine synthase (SelA). Here we show by fluorescence anisotropy binding assays and electron microscopical symmetry analysis that the SelA-tRNA(sec) binding stoichiometry is of one tRNA(sec) molecule per SelA monomer (1:1) rather than the 1:2 value proposed previously. Negative stain transmission electron microscopy revealed a D5 pointgroup symmetry for the SelA-tRNA(sec) assembly both with and without tRNA(sec) bound. Furthermore, SelA can associate forming a supramolecular complex of stacked decamer rings, which does not occur in the presence of tRNA(sec). We discuss the structure-function relationships of these assemblies and their regulatory role in bacterial selenocysteyl-tRNA(sec) synthesis., (Copyright © 2013. Published by Elsevier B.V.)

Searching for new promising metal-based hits against Trypanosoma cruzi and Leishmania parasites, two related oxidovanadium(IV) N-acylhydrazone complexes, [V(IV)O(LASSBio1064-2H)(H2O)], 1, and [V(IV)O(LASSBio1064-2H)(phen)]·(H2O), 2, where LASSBio1064=(E)-N'-(2-hydroxybenzylidene-4-chlorobenzohydrazide and phen = 1,10-phenanthroline, were synthesized and characterized in the solid state and in solution by elemental analysis, conductimetric measurements and ESI-MS, FTIR, EPR and (51)V NMR spectroscopies and were evaluated on T. cruzi and Leishmania major. In addition, their unspecific cytotoxicity was tested against murine macrophages. Furthermore, to provide insight into the possible mechanism of its antiparasitic action, [VO(LASSbio1064-2H)(phen)].(H2O) was tested for its DNA interaction ability on plasmid DNA by atomic force microscopy (AFM) and on CT DNA by using DNA viscosity measurements and fluorescence spectroscopy. Both complexes were active in vitro against the epimastigote form of T. cruzi (Tulahuen 2 strain) showing IC50 values of the same order or significantly lower than that of the reference trypanosomicidal drug Nifurtimox. However, only the mixed-ligand oxidovanadium(IV) complex 2, which includes phen in its coordination sphere, showed activity on L. major promastigotes with a IC50 value of 22.1 ± 0.6 μM. The compounds show low toxicity on mammalian cells (IC50 > 100 μM). DNA interaction studies showed that the mixed-ligand complex is able to interact with this biomolecule probably through an intercalative mode, pointing out at DNA as a potential target in the parasite. The results suggest that [V(IV)O(LASSBio1064-2H)(phen)]·(H2O) may be a promising compound for further drug development stages., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Background: The prevalence of cardiovascular disease (CVD) has increased steadily in recent years. Literature data show that about 35% of atherosclerotic events occur in the absence of classic risk factors, requiring a broader assessment of the individual to better characterize the risk. Lipid Tetrad Index (LTI) and Lipid Pentad Index (LPI) constitute a new and efficient evaluation of the lipid profile and CVD risk., Objective: This study assessed LTI and LPI in undergraduate students, seeking to establish the parameters of these indices in healthy subjects and correlate them with the conventional lipid profile., Methods: The study included 110 students, 48 (44%) males and 62 (56%) females, mean age 20.9 ± 1.7. Apolipoprotein-AI, apolipoprotein B, total cholesterol, lipoprotein(a), triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were assessed, using specific diagnostic methods. LTI and LPI indices were calculated using the equations LTI = [total cholesterol x triglycerides x lipoprotein(a) / HDL] and LPI = [total cholesterol x triglycerides x lipoprotein(a) x apolipoprotein B/apolipoprotein-AI], respectively., Results: LTI and LPI values were significantly higher in females compared to males. As for the other parameters, there were significant differences between males and females only regarding total cholesterol, HDL and apolipoprotein-AI. There were significant and positive correlations between LDL and LTI and between LDL and LPI., Conclusions: Findings indicate that both LTI and LPI were associated with LDL, a parameter not used to calculate lipid indices and widely used in clinical practice for cardiovascular risk assessment.

Transthyretin (TTR) is a homotetrameric protein that circulates in plasma and cerebral spinal fluid (CSF) whose aggregation into amyloid fibrils has been associated with at least two different amyloid diseases: senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). In SSA aggregates are composed of WT-TTR, while in FAP more than 100 already-described variants have been found in deposits. Until now, TTR-related diseases have been untreatable, although a new drug called Tafamidis has been approved only in Europe to specifically treat V30M patients. Thus, new strategies are still necessary to treat FAP caused by other variants of TTR. TTR has two channels in the dimer interface that bind to the hormone thyroxin and that have been used to accommodate anti-amyloidogenic compounds. These compounds stabilize the tetramers, rendering TTR less amyloidogenic. Here, we investigated the effects of three non-steroidal anti-inflammatory compounds-sulindac (SUL), indomethacin (IND) and lumiracoxib (LUM)-as tetramer stabilizers and aggregation inhibitors. WT-TTR and the very aggressive TTR variant L55P were used as models. These compounds were able to stabilize TTR against high hydrostatic pressure (HHP), increasing the ΔGf by several kcal. They were also effective in inhibiting WT-TTR and L55P acid- or HHP-induced aggregation; in particular, LUM and IND were very effective, inhibiting almost 100% of the aggregation of both proteins under certain conditions. The species formed when aggregation was performed in the presence of these compounds were much less toxic to cells in culture. The crystal structures of WT-TTR bound to the three compounds were solved at high resolution, allowing the identification of the relevant protein:drug interactions. We discuss here the ligand-binding features of LUM, IND and SUL to TTR, emphasizing the critical interactions that render the protein more stable and less amyloidogenic.

Amylin is a 37-aminoacid pancreatic protein that exerts control over several metabolic events such as glycemia and lacticemia. Amylin has long been shown to induce increases in arterial plasma glucose. We decided to investigate whether amylin plays additional roles in the glucose metabolism. We evaluated glucose homeostasis using whole blood from the tail tip of fasting, conscious, unrestrained normal and streptozotocyn-induced diabetic mice following subcutaneous administration of mouse amylin. Subcutaneous injection of 1 μg mouse amylin caused a transient decrease in whole blood glucose in both normal and diabetic mice in the absence of insulin. The blood glucose levels were lowest approximately 2 hours after amylin administration, after that they gradually recovered to the levels of the control group. The hypoglycemic effect followed a dose-dependent response ranging from 0.1 to 50 µg / mouse. These results reveal the ability for amylin in the direct control of glycemia at low doses in the absence of insulin.

Insulin shows a complex equilibrium between monomers and hexamers, involving varying conformers and association states. We sought to perform a structural characterization of the fast-acting human insulin variant B28Asp ("aspart"). Small-angle X-ray scattering measurements reveal similar globular behavior in both the aspart and regular human insulin, with a Rg of 19Å and a Dmax of approximately 50Å, indicating similar mean quaternary assembly distribution. Crystallographic assays revealed a T3R3 assembly of the aspart insulin formed by the TR dimer in the asymmetric unit, with all the first 8 residues of the B chain in the R-state monomer in helical conformation and the participation of its B3Asn in the stabilization of the hexamer. Our data provide access to novel structural information on aspart insulin such as an aspart insulin dimer in solution, the aspart insulin in T conformation and a pure R-state conformer establishing a T3R3 assembly, providing further insight on the stepwise conformational transition and assembly of this fast-insulin., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A subtractive cDNA library from cotton buds was constructed to prospect for differentially expressed genes related to early bud development. A library was constructed and 768 cDNA sequences were obtained, comprising 168 clusters, with 126 contigs and 42 singlets. Both the Gossypium as well as Arabidopsis databases were utilized for the in silico analysis, since some genes identified in cotton have not yet been studied for functionality, although they have homology with genes from other species. The transcriptome revealed a large number of transcripts, some of them with unknown function, and others related to pollen development, pollen tubes, ovules, and fibers at different stages. The most populated contig was identified as fiber from 0-10 days after anthesis, with 12 reads. The success and novelty rates generated from the library were 67 and 51%, respectively. The information obtained here will provide a framework for research on functional cotton genomics.

Neglected diseases represent a major health problem. It is estimated that one third of the world population is infected with tuberculosis and additionally Leishmaniosis and Chagas disease affect approximately 30 million people. N-Acylhydrazone moiety is a repeated functional group present in several prototypes and drug candidates for these neglected diseases. On the other hand, furoxan system has been studied as pharmacophore for Leishmaniosis and Chagas diseases. Here we report on the design and preparation of forty hybrid furoxanyl N-acylhydrazones and on their activity on Mycobacterium tuberculosis, H37Rv and MDR strains, Trypanosoma cruzi, and Leishmania amazonensis. Among them, four derivatives displayed excellent to good selectivity indexes against the three different microorganisms. Hybrid compound N'-(4-phenyl-3-furoxanylmethylidene)isoniazide 9 showed the best antibacterial profile with MIC value 4.5 lesser than the value for the reference isoniazid against MDR strain. Furoxanyl N-acylhydrazone (E)-2-methyl-N'-(4-phenyl-3-furoxanylmethylidene)-4H-imidazo[1,2-a]pyridine-3-carbohydrazide 15 was ten-fold more potent against T. cruzi Amastigotes than the standard drug nifurtimox. On the other hand, derivatives (E)-N'-(5-benzofuroxanylmethylidene)benzo[d][1,3]dioxole-5-carbohydrazide 25 and (E)-N'-(4-hydroxy-3-methoxyphenylmethylidene)-3-methylfuroxan-4-carbohydrazide 37 emerged as leads for the development of new leishmanicidal agents. The adequate stability, in simulated biological system and plasma, and the lack of mutagenicity of these derivatives allow us to propose them as candidates for further pre-clinical studies., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Unlabelled: Human T cell lymphotropic virus type 1 (HTLV-1) is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While the immune response to HTLV-1 infection is polarized to the Th1-type, chronic helminth infections drive the Th2- and T regulatory-type, and are able to downregulate the inflammatory response in some autoimmune diseases., Objective: To evaluate whether Schistosoma spp. antigens alter the in vitro cytokine response in HTLV-1 infection., Methods: The recombinant Schistosoma antigens Sm29 and ShTSP2 (tetraspanin) and PIII, a fraction of the Schistosoma mansoni adult worm antigen were added to peripheral blood mononuclear cell (PBMC) cultures of HTLV-1-infected individuals and the levels of interferon (IFN)-γ and interleukin (IL)-10 in the supernatants were measured using the ELISA sandwich technique., Results: Compared to the levels of cytokine in nonstimulated cultures, the levels of IFN-γ were reduced in 50, 47 and 50% of patients by the presence of Sm29, ShTsp2 and PIII, respectively. The downregulation of IFN-γ production in the presence of Sm29 antigen was observed mainly in subjects who had lower basal levels of this cytokine. The levels of IL-10, however, increased by the addition of the three antigens in the cultures in 74, 62 and 44% of individuals, respectively. In addition, there was a decrease in the ratio of IFN-γ/IL-10 levels in cultures stimulated with Sm29 and ShTSP2 when compared to nonstimulated ones., Conclusions: The Schistosoma spp. antigens used in this study were able to downmodulate IFN-γ production in vitro in HTLV-1 infection. This may be associated with the increased levels of IL-10 induced by the antigens., (Copyright © 2013 S. Karger AG, Basel.)

Aim: In the search for new antithrombotic drug candidates, the synthesis and anti-platelet activity of a new series of N-acylhydrazones that were designed as thrombin inhibitors has been previously described. The aim of this work was to further characterize the effects of these compounds on thrombin-induced platelet aggregation and induced thrombosis in vivo., Methods: In this work, four compounds were tested, LASSBio-693, 694, 743 and 752, on platelet aggregation induced by thrombin, ADP and TRAP-4A. These compounds were further tested using a mouse pulmonary thromboembolism model induced by collagen (500 µg/kg) and norepinephrine (80 µg/kg) or thrombin (2,000 UI), and a deep venous thrombosis model., Results: At 200 µM, the compounds showed between 36% and 82% inhibition (for L-743 and L-752, respectively) of thrombin-induced platelet aggregation. The receptor agonist of PAR-4, TRAP-4A (250 µM), was used and inhibition between 43% and 77% was observed for each compound (200 µM).Compounds LASSBio-752 and 743 were the most effective in the venous thrombosis model, increasing the survival of the treated animals to 63% and 46%, respectively, in the model of collagen-induced thromboembolism and increasing to 80% (both) in the thrombin-induced model. LASSBio 743 was more effective for deep vein thrombosis, reducing the weight of the thrombus by approximately 70%., Conclusion: All compounds were administered orally and have shown effective antithrombotic action independently of the thrombotic stimulus. These results indicate that compounds LASSBio-743 and 752 are potential candidates for the treatment of cardiovascular diseases.

In this paper we report the design, synthesis and pharmacological evaluation of a new series of phenyl sulfonamide derivatives 2a-h and 3-8 planned by structural modification on the anti-inflammatory prototype LASSBio-468 (1). Among the synthesized analogues, the tetrafluorophthalimide LASSBio-1439 (2e) stands out showing an in vitro anti-TNF-α effect similar to the standard thalidomide. The relevance of tetrafluorination of the phthalimide nucleus was also confirmed by the anti-inflammatory profile of 2e, through oral administration, in a murine model of pulmonary inflammation. The corresponding tetrafluorocarboxyamide metabolite LASSBio-1454 (15), generated from partial hydrolysis of the derivative 2e, presented a significant in vitro effect and a pronounced anti-inflammatory activity in vivo.

LASSBio-985 is a sulfonamide compound designed as a simplified structure of a nonselective phosphodiesterase type 4 (PDE-4) inhibitor that promotes vasodilatory activity in vitro. PDE are enzymes responsible for the hydrolysis of cyclic adenosine 3',5'- monophosphate and cyclic guanosine 3',5'-monophosphate. Five different isozymes of PDE are found in vascular smooth muscle (PDE1-PDE5). Aortic rings, with or without endothelium, from male normotensive and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. Blood pressure was measured in Wistar Kyoto (WKY) rats and SHR during intravenous infusion of LASSBio-985 (10 mg/kg/min) during 15 min. LASSBio-985 induced a concentration-dependent vasodilation in aortic rings from normotensive and SHR, which was almost completely inhibited in endothelium-denuded vessels. Vasodilatory activity was also reduced in endothelium-intact aortic rings that had been pretreated with N(ω)-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor and 1H-[1,2,4]oxadiazolod[4,3-a]quinoxalin-1-one (ODQ), a guanylate cyclase inhibitor. LASSBio-985-induced vasodilation was also inhibited by sildenafil (100 μm) and SQ 22536, a PDE5 inhibitor and adenylate cyclase inhibitor, respectively. To evaluate the involvement of some endothelial receptors, atropine, diphenhydramine, HOE 140, naloxone, propranolol, indomethacin, and wortmannin were tested, but none inhibited the effects of LASSBio-985. The residual effect observed on endothelium-denuded aortic rings was abolished by nicardipine, a voltage-sensitive-Ca(2+)-channel blocker. Intravenous infusion of LASSBio-985 (10 mg/kg/min) significantly reduced systolic and diastolic pressures in both WKY and SHR. LASSBio-985 is a compound with vasodilatory activity, which could be consequent to PDE1 inhibition and voltage-sensitive-Ca(2+)-channel blockade., (© 2011 The Authors Fundamental and Clinical Pharmacology © 2011 Société Française de Pharmacologie et de Thérapeutique.)

Introduction: A retrospective study was conducted to assess the occurrence of blood donations that were ineligible due to Chagas disease infection from 1995 to 2009 at the Uberaba Regional Blood Center (HRU), Brazil, verify the tendency of this ineligibility, and describe the epidemiologic profile of the donors., Methods: Retrospective studies of serological ineligibility due to Chagas disease, statistical analysis by means of the chi-square test and odds ratio, study of the tendencies using a dispersion graph and the linear correlation coefficient (r) were performed., Results: In the period under study, a 0.2% serum prevalence of ineligibility due to Chagas disease was found, with a significant drop in ineligible donations from 2001 to 2009. Among the serum positive-donors, there was a significant predominance among those aged 30 years or above and non-single individuals., Conclusions: The results show a rate of occurrence that is lower than that described in literature, as well as a progressive drop during the 15 years under assessment. Such results are a consequence of systematic combat of the vector since the 70s and the progressive and consistent increase of returning donors, resulting in a drop of the contamination risk factor by means of blood transfusion and in the improvement of the quality of hemotherapy practices in the HRU.

In this paper we report the design, synthesis, antinociceptive and anti-inflammatory activities of a series of benzothiazine N-acylhydrazones 14a–h, planned by structural modification of piroxicam (1), a non steroidal anti-inflammatory drug. Among the synthesized analogues, compounds 14f (LASSBio-1637) and 14g (LASSBio-1639) were identified as novel antinociceptive and anti-inflammatory prototypes, active by oral administration, acting by a mechanism of action that seems to be different from that of piroxicam, since they were inactive as an inhibitor of cyclooxygenase (COX-1 and COX-2) at concentrations of 10 mM.

Background and Objectives: Lead poisoning, also Saturnism, results from chronic lead poisoning, common after occupational exposure. Projectiles retained in the body may result in increased levels of plasma lead with numerous clinical implications, particularly neurological. We report a case of a symptomatic patient, undiagnosed, whose diagnosis was made during the preanesthesia evaluation., Case Report: The patient was attended at our hospital to remove a bullet lodged in his left knee 14 years ago, presenting with polyneuropathy without investigation. During the preanesthetic visit, saturnism was hypothesized and confirmed by high plasma lead levels (129 μg.dL(-1)). Surgery was performed under general anesthesia before starting lead chelation. During anesthesia, the patient developed apnea, without chest-wall rigidity after administration of fentanyl (50 μg)., Conclusion: Lead poisoning interferes with the function of various organs and systems, alters oxidative metabolism and intracellular signaling mechanisms. Neurological involvement, with reduced neural conduction, deserves special attention from anesthesiologists., (Copyright © 2012 Elsevier Editora Ltda. All rights reserved.)

Purpose: To investigate which muscular maneuvers provide larger electric activity (EA) of the suprahyoid (SH) and infrahyoid (IH) muscles to be used as surface electromyography (SEMG) signal normalization reference., Methods: The electrical potentials of the SH and IH muscles of 12 subjects were evaluated using six muscular maneuvers, involving the position of the tongue and effort. It was selected as maximum voluntary sustained activity maneuver, the one having the minor coefficient of variation and the smallest value for each muscle group. The EA signal was converted using the root mean square in microvolts. It was considered then the maximum signal of each maneuver as the difference between the mean of three measures and the resting potential., Results: The maneuvers that provided higher mean potentials with minor coefficient of variation and smallest P value were incomplete swallowing (IS) with effort (mean potential equal to 56.73±8.68 with coefficient of variation of 15.30%) in SH group, and tongue retracted with mouth open (TROM, mean potential equal to 46.57±7.83 with coefficient of variation of 16.81%) in IH group., Conclusion: The IS with effort and TROM maneuvers should be considered for signal normalization in these muscles, respectively, and may provide conditions for using the SEMG in voice clinic., Significance: The use of normalization standards in researches of SH and IH muscles in the voice area will allow comparisons among future works., (Copyright © 2012 The Voice Foundation. Published by Mosby, Inc. All rights reserved.)

Introduction:  Among people affected by cancer, the impairment of quality of life of people affected by cancer can cause have devastating effects. The self-image of patients after post-laryngectomyzed patients may be find themselves compromised, affecting the quality of life in this population., Objective:  To characterize quality of life in related to communication in people who have undergone went total laryngectomy surgery., Methods:  This is an observational study, with a cross-sectional and descriptive series. Design of series study. The sample were comprised 15 patients interviewed the period from January to February of 2011. We used the Quality Protocol for Life Communication in Post-laryngectomy adapted from Bertocello (2004); which this questionnaire contains 55 questions. The protocol was organized from the nature of using responses classified as positive and negative aspects, proposals in with respect to five 5 communication domains: family relationships, social relationships, personal analysis; morphofunctional aspect, and use of writing. To promote and guarantee the autonomy of the respondents, was examiners made use of used assistive technology with the Visual Response Scale., Results:  The responses that total laryngectomy compromises the quality of life in communication amounted to 463 occurrences (65.7%), and that who responses suggesting good quality of life were represented with amounted to 242 occurrences (34.3%), from a total of 705 occurrencesresponses. From Among the five 5 Communication domains, four 4 had percentages of above 63% for occurrences of negative content for impact on communication. Appearance Morphofunctional appearance gave the had the highest percentage of negative content, amounting to 77.3% of cases., Conclusions:  The results showed important limitations of a personal and social nature due to poor communication with their peers. Thus, there is a need for multidisciplinary interventions that aim to minimize the entrapment of negative impact on these people communication among these patients.

Introduction:  Total laryngectomy creates deglutition disorders and causes a decrease in quality of life Aim: To describe the impact of swallowing and quality of life of patients after total laryngectomy., Method:  A case series study. Patients completed a Swallowing and Quality of Life questionnaire composed of 44 questions assessing 11 domains related to quality of life (burden, eating duration, eating desire, frequency of symptoms, food selection, communication, fear, mental health, social functioning, sleep, and fatigue). The analysis was performed using descriptive statistics, including measures of central tendency and variability., Results:  The sample comprised 15 patients who underwent total laryngectomy and adjuvant radiotherapy. Of these, 66.7% classified their health as good and 73% reported no restrictions on food consistency. The domains "communication" and "fear" represented severe impact and "eating duration" represented moderate impact on quality of life. The items with lower scores were: longer time to eat than others (domain "eating duration"), cough and cough to remove the liquid or food of the mouth when they are stopped (domain "symptom frequency"), difficulties in understanding (domain "communication") and fear of choking and having pneumonia (domain "fear")., Conclusion:  After total laryngectomy, patients report that swallowing issues have moderate to severe impact in "communication," "fear," and "eating duration" domains.

Transthyretin (TTR) is a carrier protein involved in human amyloidosis. The development of small molecules that may act as TTR amyloid inhibitors is a promising strategy to treat these pathologies. Here we selected and characterized the interaction of flavonoids with the wild type and the V30M amyloidogenic mutant TTR. TTR acid aggregation was evaluated in vitro in the presence of the different flavonoids. The best TTR aggregation inhibitors were studied by Isothermal Titration Calorimetry (ITC) in order to reveal their thermodynamic signature of binding to TTRwt. Crystal structures of TTRwt in complex with the top binders were also obtained, enabling us to in depth inspect TTR interactions with these flavonoids. The results indicate that changing the number and position of hydroxyl groups attached to the flavonoid core strongly influence flavonoid recognition by TTR, either by changing ligand affinity or its mechanism of interaction with the two sites of TTR. We also compared the results obtained for TTRwt with the V30M mutant structure in the apo form, allowing us to pinpoint structural features that may facilitate or hamper ligand binding to the V30M mutant. Our data show that the TTRwt binding site is labile and, in particular, the central region of the cavity is sensible for the small differences in the ligands tested and can be influenced by the Met30 amyloidogenic mutation, therefore playing important roles in flavonoid binding affinity, mechanism and mutant protein ligand binding specificities., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Iron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex.

Phthalimide derivatives containing furoxanyl subunits as nitric oxide (NO)-donors (3a-g) were designed, synthesized, and evaluated in vitro and in vivo for their potential uses in the oral treatment of sickle cell disease symptoms. All compounds (3a-g) demonstrated NO-donor properties at different levels. Moreover, compounds 3b and 3c demonstrated analgesic activity. Compound 3b was determined to be a promising drug candidate for the aforementioned uses, and it was further evaluated in K562 culture cells to determine its ability to increase levels of γ-globin expression. After 96 h at 5 μM, compound 3b was able to induce γ-globin expression by nearly three times. Mutagenic studies using micronucleus tests in peripheral blood cells of mice demonstrated that compound 3b reduces the mutagenic profile as compared with hydroxyurea. Compound 3b has emerged as a new leading drug candidate with multiple beneficial effects for the treatment of sickle cell disease symptoms and provides an alternative to hydroxyurea treatment.

In this study, we examined the effects of LASSBio-965 (N-[2-(3,4-dimethoxyphenyl) ethyl]-benzenesulfonamide), a compound designed as a simplified structure of a non-selective phosphodiesterase 4 inhibitor, on vascular smooth muscle in vitro as well as in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension. LASSBio-965 (50 mg/kg) treatment caused a significant decrease in right systolic ventricular pressure (32.47 ± 3.09 mmHg) compared to the MCT-vehicle group (51.88 ± 3.23 mmHg; P<0.05) and in the ratio of right ventricular weight to left ventricular weight plus septum (0.42 ± 0.03 g compared to 0.59 ± 0.06 g, respectively; MCT-vehicle group; P<0.05). LASSBio-965 induced a concentration-dependent relaxation of rat aortic rings, which was decreased by mechanical removal of the endothelium. Milrinone, rolipram, and sildenafil reduced the maximum relaxation (100%) to 22.4 ± 5.8, 69.5 ± 5.6 and 80.1 ± 10.7%, respectively (P<0.05). Maximum relaxation responses of aortic and pulmonary artery rings were decreased in the MCT-vehicle group (54.80 ± 5.69 and 35.87 ± 4.78, respectively) compared to the control (91.51 ± 4.79 and 54.32 ± 2.39, respectively) but improved with LASSBio-965 treatment (50mg/kg; 88.43 ± 4.54 and 59.36 ± 4.83, respectively). These results indicate that LASSBio-965 can attenuate the pulmonary arterial hypertension in an animal model most likely through the nonselective inhibition of phosphodiesterases 3, 4, and 5., (Copyright © 2012 Elsevier B.V. All rights reserved.)

p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Several p38 MAPK inhibitors have been developed as drug candidates to treatment of autoimmune disorders, such as rheumatoid arthritis. In this paper we reported the docking, synthesis and pharmacological activity of novel urea-derivatives (4a-e) designed as p38 MAPK inhibitors. These derivatives presented good theoretical affinity to the target p38 MAPK, standing out compound 4e (LASSBio-998), which showed a better score value compared to the prototype GK-00687. This compound was able to reduce in vitro TNF-α production and was orally active in a hypernociceptive murine model sensible to p38 MAPK inhibitors. Otherwise, compound 4e presented a dose-dependent analgesic effect in a model of antigen (mBSA)-induced arthritis and anti-inflammatory profile in carrageenan induced paw edema, indicating its potential as a new antiarthritis prototype., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

The syntheses of a new 1,4,7,10-tetraazacyclododecane (cyclen) derivative bearing a picolinate pendant arm (HL1), and its 1,4,8,11-tetraazacyclotetradecane (cyclam) analogue HL2, were achieved by using two different selective-protection methods involving the preparation of cyclen-bisaminal or phosphoryl cyclam derivatives. The acid-base properties of both compounds were investigated as well as their coordination chemistry, especially with Cu(2+), in aqueous solution and in solid state. The copper(II) complexes were synthesized, and the single crystal X-ray diffraction structures of compounds of formula [Cu(HL)](ClO(4))(2)·H(2)O (L = L1 or L2), [CuL1](ClO(4)) and [CuL2]Cl·2H(2)O, were determined. These studies revealed that protonation of the complexes occurs on the carboxylate group of the picolinate moiety. Stability constants of the complexes were determined at 25.0 °C and ionic strength 0.10 M in KNO(3) using potentiometric titrations. Both ligands form complexes with Cu(2+) that are thermodynamically very stable. Additionally, both HL1 and HL2 exhibit an important selectivity for Cu(2+) over Zn(2+). The kinetic inertness in acidic medium of both complexes of Cu(2+) was evaluated by spectrophotometry revealing that [CuL2](+) is much more inert than [CuL1](+). The determined half-life values also demonstrate the very high kinetic inertness of [CuL2](+) when compared to a list of copper(II) complexes of other macrocyclic ligands. The coordination geometry of the copper center in the complexes was established in aqueous solution from UV-visible and electron paramagnetic resonance (EPR) spectroscopy, showing that the solution structures of both complexes are in excellent agreement with those of crystallographic data. Cyclic voltammetry experiments point to a good stability of the complexes with respect to metal ion dissociation upon reduction of the metal ion to Cu(+) at about neutral pH. Our results revealed that the cyclam-based ligand HL2 is a very attractive receptor for copper(II), presenting a fast complexation process, a high kinetic inertness, and important thermodynamic and electrochemical stability.