Copper(II) complexes of a furan-containing aroylhydrazonic ligand: syntheses, structural studies, solution chemistry and interaction with HSA.

Copper(II) complexes have become a potential alternative to the use of platinum drugs in cancer therapy due to their multi-target mode of action. In this context, we report the syntheses of new mononuclear and dinuclear coordination compounds of this element, 1 and 2, derived from the ligand 5-methylsalicylaldehyde 2-furoyl hydrazone (H2L). All three compounds were structurally and spectroscopically characterized, both in the solid state and in solution. In 1, Cu is coordinated by three donor-atoms from the hydrazonic ligand and one chloride ion. H2L is deprotonated at the phenol oxygen. The dinuclear complex 2 is, on the other hand, a dimeric form of 1 in which the chloride ions of a pair of mononuclear units are lost and phenoxo bridges take their places, double-connecting the metal centres and resulting in a single species with the ligand fully deprotonated. The compounds were fairly stable in aqueous medium at room temperature. An experimental-theoretical combined approach demonstrated that all of them are able to bind human serum albumin (HSA), although at different sites and with diverse stoichiometries and affinities (as concluded by the calculated binding energies). In view of this, and due to the well-known antiproliferative activity of hydrazone-containing copper complexes, we consider the compounds presented in here promising, and believe that they deserve more profound studies regarding the assessment of their potential against tumour cell lines.

Distributed functional-group polarizabilities in polypeptides and peptide clusters toward accurate prediction of electro-optical properties of biomacromolecules.

CONTEXT: Aiming at accurately predicting electro-optical properties of biomolecules, this work presents distributed atomic and functional-group polarizability tensors for a series of polypeptides and peptide clusters constructed from glycine and its residuals. By partitioning the electron density using the quantum theory of atoms in molecules, we demonstrated a very good transferability of the group polarizabilities. We were able to identify and extract the most efficient functional groups capable of generating the largest electrical susceptibility in condensed phases. Both the isotropic polarizability and its anisotropy were used to understand the way functional groups act as sources of linear optical responses, how they interact with each other reinforcing the macroscopic optical behavior within the material, and how covalent bonds and non-covalent interactions, such as hydrogen bonds, determine refractive indices and birefringence. Particular attention is devoted to the peptide bonds as they provide links to build biomacromolecules or polymers. An adequate quantum-mechanical treatment of at least the first interaction sphere of a given functional group is required to properly describe the effects of mutual polarization, but we identified optimum cluster size and shape to better estimate polarizabilities and dipole moments of larger molecules or molecular aggregates from the knowledge of the electron density of a central molecule or amino acid residual that is representative of the bulk. The strategy outlined here is a fast yet effective tool for estimating the optical properties of proteins but could eventually find application in the rational design of optical organic materials as well. METHODS: Electronic-structure calculations were performed on the Gaussin16 program at the DFT level using the CAMB3LYP functional and the double-ζ quality Dunning basis set aug-cc-pVDZ. Electron density partitioning followed the concepts of the Quantum Theory of Atoms and Molecules (QTAIM) and was performed using the AIMAll program. The locally developed Polaber routine was applied to calculate dipole moment vectors and polarizability tensors. It was amended to include the effects of the local field on a given central molecule by means of a modified Atom-Dipole Interaction Model (ADIM).

New mescaline-related N-acylhydrazone and its unsubstituted benzoyl derivative: Promising metallophores for copper-associated deleterious effects relief in Alzheimer's disease.

Alzheimer's disease (AD) is related to the presence of extracellular aggregated amyloid-ß peptide (Aß), which binds copper(II) with high affinity in its N-terminal region. In this sense, two new 1-methylimidazole-containing N-acylhydrazonic metallophores, namely, X1TMP and X1Benz, were synthesized as hydrochlorides and characterized. The compound X1TMP contains the 3,4,5-trimethoxybenzoyl moiety present in the structure of mescaline, a natural hallucinogenic protoalkaloid that occurs in some species of cacti. Single crystals of X1Benz, the unsubstituted derivative of X1TMP, were obtained. The experimental partition coefficients of both compounds were determined, as well as their apparent affinity for Cu2+ in aqueous solution. Ascorbate consumption assays showed that these N-acylhydrazones are able to lessen the production of ROS by the Cu(Aß)-system, and a short-time scale aggregation study, measured through turbidity and confirmed by TEM images, revealed their capacity in preventing Aß fibrillation at equimolar conditions in the presence and absence of copper. 1H15N HSQC NMR experiments demonstrated a direct interaction between Aß and X1Benz, the most soluble of the compounds. The Cu2+ sequestering potential of this hydrazone towards Aß was explored by 1H NMR. Although increasing amounts of X1Benz were unexpectedly not efficient at removing the metal-induced perturbations in Aß backbone amides, the broadening effects observed on the compound's signals indicate the formation of a ternary Aß­copper-X1Benz species, which can be responsible for the observed ROS-lessening and aggregation-preventing activities. Overall, the N-acylhydrazones X1TMP and X1Benz have shown promising prospects as agents for the treatment of AD.

Memantine-Derived Schiff Bases as Transdermal Prodrug Candidates.

Condensation reactions of salicylaldehyde, 2-pyridinecarboxaldehyde, and pyridoxaldehyde with memantine (Me) produced novel memantine-derived Schiff bases (1-3). Speciation predictions and calculations of Log P, Log D, and of the percentage (%) of neutral species for (1-3) were carried out. In comparison with Me, the Schiff bases presented increased log P and log D in all cases and pH values, suggesting higher hydrophobicity. The determined solubilities in n-octanol were 34.7 mg/mL for memantine hydrochloride and 67.3 mg/mL for (3). According to the molecular weights and calculated logP, compounds (1-3) are suitable for transdermal administration, especially compound (3). In addition, hydrolysis of 3 with the release of pyridoxal, a daily cofactor in human metabolism, was observed. The results suggested that 3 is the most promising compound and that formation of the pyridoxal Schiff base with Me might be an effective strategy to obtain a prodrug candidate with increased lipophilicity, which would be able to passively cross biological barriers during transdermal delivery and might have applications in the treatment of Alzheimer's disease and other neurological disorders.

Effect of concurrent training (aerobic+resistance) more static stretching on flexibility in women with breast cancer / Efeito do treinamento concorrente (aeróbio + resistência) mais alongamento estático na flexibilidade em mulheres com câncer de mama

Objective. was to assess flexibility in women with breast cancer who underwent concurrent training (aerobic+resistance) (CT) more static stretching. Methods. This was a controlled pilot study, with 31 women (age 30 to 59) under breast cancer treatment, 14 women were allocated to a training group (TG) who underwent CT more static stretching, concomitant to hospital treatment and 17 women for the control group (CG) who only underwent hospital treatment. The CT more static stretching was performed in 12 weeks with 5 sessions per week, three sessions (aerobic+resistance) and two sessions (stretching exercises) on alternate days. The flexibility of the shoulder was measured by means of the 360º Sanny pendulum goniometer and the flexibility of the lower limbs was assessed through the sit-and-reach test. Data were analyzed using repeated measures ANOVA Test and Bonferroni Post-hoc using SPSS 21 software, with α of 5%. Results. The TG presented increased flexibility in the horizontal abduction of the right shoulder (p=0.001) and in the lower limbs (p<0.001), but the CG showed a reduction in the horizontal abduction of the right shoulder (p=0.003). The effect size for horizontal abduction of the right shoulder was medium (p=0.508) and for the lower limbs was large (p=0.839). Conclusion. CT more static stretching may be a therapeutic intervention to increase flexibility of upper and lower limbs in women with breast cancer. (AU)

Objetivo. Avaliar a flexibilidade em mulheres com câncer de mama que realizaram treinamento concorrente (aeróbio + resistência) (TC) mais alongamento estático. Métodos. Este foi um estudo piloto controlado, com 31 mulheres (de 30 a 59 anos) em tratamento para câncer de mama, 14 mulheres foram alocadas em um grupo de treinamento (GT) que realizaram TC mais alongamento estático, concomitante a tratamento hospitalar e 17 mulheres para o grupo de controle (GC) que somente realizaram tratamento hospitalar. O TC mais alongamento estático foram realizados em 12 semanas com 5 sessões semanais, três sessões (aeróbia + resistência) e duas sessões (exercícios de alongamento) em dias alternados. A flexibilidade do ombro foi medida por meio do goniômetro de pêndulo 360º Sanny e a flexibilidade de membros inferiores foi avaliada por meio do teste de sentar e alcançar. Os dados foram analisados usando o Teste ANOVA de medidas repetidas e Post-hoc de Bonferroni no software SPSS 21, com α de 5%. Resultados. O GT apresentou aumento da flexibilidade na abdução horizontal do ombro direito (p=0,001) e nos membros inferiores (p<0,001), mas o GC apresentou redução da abdução horizontal do ombro direito (p=0,003). O tamanho do efeito para abdução horizontal do ombro direito foi médio (p=0,508) e para membros inferiores foi grande (p=0,839). Conclusão. O TC mais alongamento estático podem ser uma intervenção terapêutica para aumentar a flexibilidade de membros superiores e inferiores em mulheres com câncer de mama. (AU)

Mechanisms of muscle stretching exercises for reduction of low back pain: narrative review / Mecanismos de exercícios de alongamento muscular para redução de dor lombar: revisão narrativa

ABSTRACT BACKGROUND AND OBJECTIVES: Stretching exercises are present in physical training and muscle rehabilitation programs. Within the context of rehabilitation of patients with low back pain (lombalgy), there is still a gap about the mechanisms that these exercises should reduce pain and disability in these patients. The aim of this study was to investigate what are the possible mechanisms through which muscle stretching exercise could reduce pain in individuals with chronic low back pain.CONTENTS: Pain in the lumbar region is one of the most disabling pains when it comes to limitations for daily functions, so it's necessary to investigate alternatives that provide relief for these patients. As the cause of non-specific chronic low back pain is multifactorial, the treatment of the pathology occurs mainly to reduce the sensation of pain. As an alternative, the flexibility training through stretching exercises can be efficient because they generate biomechanical and sensory changes, which would result in an analgesic effect. Additionally, it's still possible that these two effects occur together to explain the reduction in low back pain after performing stretching exercises. CONCLUSION: There is theoretical basis in the literature to support the performance of stretching exercises as a non-pharmacological strategy for the treatment of chronic low back pain. Biomechanical and neurophysiological mechanisms can be pointed out to explain these benefits.

RESUMO JUSTIFICATIVA E OBJETIVOS: Exercícios de alongamento estão presentes em programas de treinamento físico e reabilitação muscular. Dentro do contexto da reabilitação de indivíduos com dor na região lombar (lombalgia), ainda existe uma lacuna sobre os mecanismos pelos quais esses exercícios reduzem dor e incapacidade nesses pacientes. O objetivo deste estudo foi descrever os possíveis mecanismos pelos quais o exercício de alongamento pode reduzir dor em indivíduos com lombalgia crônica. CONTEÚDO: A dor na região lombar é uma das dores mais incapacitantes quando se trata de limitações para as funções no cotidiano. Por isso, é necessário investigar alternativas que possam proporcionar o seu alívio nesses pacientes. Considerando que a causa da lombalgia crônica não específica é multifatorial, o tratamento desta doença ocorre principalmente na tentativa de reduzir a sensação dolorosa. Como alternativa, o treinamento da flexibilidade por meio de exercícios de alongamento pode agir reduzindo a dor lombar por gerarem alterações biomecânicas e sensoriais que resultam em efeito analgésico. Adicionalmente, ainda é possível que esses dois efeitos possam atuar em conjunto para explicar a redução da dor lombar após a realização de exercícios de alongamento. CONCLUSÃO: Existe suporte teórico na literatura para sustentar a realização dos exercícios de alongamento como estratégia não farmacológica para o tratamento da dor lombar crônica. Mecanismos biomecânicos e neurofisiológicos poderiam ser apontados para explicar tais benefícios.

Theoretical and X-Ray Evidence of Electrostatic Phosphonium anti and gauche Effects.

Sulphur, not phosphorus, is the only known third-row element capable of experiencing an electrostatic gauche effect with fluorine. Some six-membered rings containing an endocyclic phosphorus atom and a ß-fluorine substituent that can interconvert to axial (gauche relative to phosphorus) and equatorial positions were then analysed. While phosphines do not establish an electrostatic attraction between fluorine and phosphorus, some oxidised forms exhibit surprising stability for the sterically disfavoured axial orientation. Because the nature of this behaviour was not obvious, since an intramolecular hydrogen bond can appear, a phosphonium derivative was further studied and its axial conformation was found to be highly stable. A preference for the gauche arrangement appears even for the acyclic and sterically hindered (2-fluoroethyl)triphenylphosphonium cation. On the other hand, (ethane-1,2-diyl)bis(phosphonium) cations are exclusively in anti conformation due to an (+/+)-electrostatic repulsion between the positively charged phosphonium groups.

Full Equilibrium Picture in Aqueous Binary and Ternary Systems Involving Copper(II), 1-Methylimidazole-Containing Hydrazonic Ligands, and the 103-112 Human Prion Protein Fragment.

In this work, we describe two novel 1-methylimidazole N-acylhydyrazonic ligands and their interaction with copper(II) in solution. Binary systems constituted by each of these hydrazones and the metal ion were studied by potentiometric titrations. The magnitude of their affinities for zinc(II) was also determined for the sake of comparison. Additionally, a full evaluation of the copper(II) chelation profile of the new ligands in ternary systems containing a human prion protein fragment was performed. Mixed ligand complexes comprising the HuPrP103-112 fragment, copper(II) ions, and an N-acylhydrazone were characterized by potentiometry, ultraviolet-visible spectroscopy, and circular dichroism. Some of these species were also identified by electrospray ionization mass spectrometry and unequivocally assigned through their isotopic distribution pattern. To the best of our knowledge, this is the first report concerning the stability of ternary complexes involving a hydrazonic metal-protein interaction modulator, copper, and a peptide. The ability of N-acylhydrazones to prevent peptide oxidation was also examined. Both ligands can partially prevent the formation of the doubly oxidized product, a process mediated by copper(II) ions. Oxidative stress is considered an important hallmark of neurodegenerative diseases such as prion-related spongiform encephalopathies. In this context, active intervention with respect to the deleterious copper-catalyzed methionine oxidation could represent an interesting therapeutic approach.

Theoretical and experimental spectroscopic investigation of new Eu(III)-FOD complex containing 2-pyrrolidone ligand.

The preparation and photoluminescent properties of the new [Eu(FOD)3(2-Pyr)2] complex (FOD = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octadionate; 2-Pyr = 2-pyrrolidone) are reported. The obtained complex was characterized by elemental analysis, complexometric titration using EDTA, infrared spectroscopy, and single-crystal X-ray diffraction studies. The coordination polyhedron of the complex is described as a distorted square antiprismatic with both 2-Pyr monodentate ligands coordinated to Eu(III) via the oxygen atoms, in neutral form, while the three FOD molecules are coordinated in the anionic form. Structural modeling at the PBE1PBE/SVP/MWB52 level of theory provided a geometry in excellent agreement with the one obtained experimentally. Spectroscopy properties such as intensity parameters (Ω2 and Ω4), radiative emission rate (Arad), and chemical partition of Arad for [Eu(FOD)3(2-Pyr)2] and [Eu(FOD)3(H2O)2] were calculated by using the QDC model with help of the semiempirical wavefunctions. The modeling of the ligand-to-metal energy transfer for both complexes was performed, allowing to obtain the theoretical emission quantum yield and to characterize the most relevant molecular orbitals involved.

Multicomponent ionic crystals of diltiazem with dicarboxylic acids toward understanding the structural aspects driving the drug-release.

Diltiazem (DIL) is a calcium channel blocker antihypertensive drug commonly used in the treatment of cardiovascular disorders. Due to the high solubility and prompt dissolution of the commercial form hydrochloride (DIL-HCl) that is closely related to short elimination drug half-life, this API is known for exhibiting an unfitted pharmacokinetic profile. In an attempt to understand how engineered multicomponent ionic crystals of DIL with dicarboxylic acids can minimize these undesirable biopharmaceutical attributes, herein, we have focused on the development of less soluble and slower dissolving salt/cocrystal forms. By the traditional solvent evaporation method, two hydrated salts of DIL with succinic and oxalic acids (DIL-SUC-H2O and DIL-OXA-H2O), and one salt-cocrystal with fumaric acid (DIL-FUM-H2FUM) were successfully prepared. An in-depth crystallographic description of these new solid forms was conducted through single and powder X-ray diffraction (SCXRD, PXRD), Hirshfeld surface (HS) analysis, energy framework (EF) calculations, Fourier Transform Infrared (FT-IR) spectroscopy, and thermal analysis (TG, DSC, and HSM). Structurally, the inclusion of dicarboxylic acids in the crystal structures provided the formation of 2D-sheet assemblies, where ionic pairs (DIL+/anion-) are associated with each other via H-bonding. Consequently, a substantial lowering in both solubility (16.5-fold) and intrinsic dissolution rate (13.7-fold) of the API has been achieved compared to that of the hydrochloride salt. These findings demonstrate the enormous potential of these solid forms in preparing of novel modified-release pharmaceutical formulations of DIL.

Evidence of the validity of the Food and Nutritional Security Scale for adolescents (ESANa). / Evidências de validade da Escala de Segurança Alimentar e Nutricional para adolescentes (ESANa).

This study aimed to develop a valid and reliable scale for assessing food and nutritional insecurity, specifically in adolescents. The initial version of the scale consisted of two subscales: perception of food insecurity and perception of nutritional security. The items were submitted to content analysis (n = 4) by a group of food and nutrition security experts, and semantic analysis (n = 20) by a group of adolescents conveniently sampled from the target population. After adjustments, the final version of the scale was applied to adolescent students (n = 425) aged 12 to 18 years (m = 14.32±0.96; CV = 6.7%). A two-factor model was the most appropriate after performing exploratory factor analysis. The subscales showed modest values of the alpha coefficient (0.69 and 0.60, respectively). Daily consumption of fruits, vegetables and soft drinks was significantly associated with higher scores in the food and nutrition security perception scale. Therefore, it is recommended to combine food access-based items with other aspects related to attitudes and behaviors towards healthy eating in order to achieve a more accurate picture of adolescent's needs and better guide public policies.

O objetivo do trabalho foi desenvolver uma escala válida e fidedigna para a avaliação de insegurança alimentar e nutricional especificamente em adolescentes. A versão inicial da escala foi composta por duas subescalas: percepção de insegurança alimentar e percepção de segurança nutricional. Os itens elaborados foram submetidos à análise de conteúdo por peritos em segurança alimentar e nutricional (n = 4) e à análise semântica por adolescentes selecionados por conveniência e oriundos da população alvo (n=20). Após ajustes, a versão final da escala foi aplicada junto a adolescentes escolares (n = 425) com idade entre 12 e 18 anos (m = 14,32±0,96; CV = 6,7%). Após realização de análise fatorial exploratória, um modelo de dois fatores foi o que se mostrou mais adequado. As subescalas avaliadas apresentaram valores modestos do coeficiente alfa (0,69 e 0,60, respectivamente). Consumo diário de frutas, verduras e refrigerantes se mostrou significativamente associado a escores mais elevados na escala de percepção de segurança alimentar e nutricional. Sugere-se a viabilidade de combinar itens com base no acesso a alimentos com outros relacionados a atitudes e práticas de alimentação saudável de modo a obter um retrato mais aproximado das necessidades dos adolescentes e melhor orientar políticas públicas.

Evidências de validade da Escala de Segurança Alimentar e Nutricional para adolescentes (ESANa) / Evidence of the validity of the Food and Nutritional Security Scale for adolescents (ESANa)

Resumo O objetivo do trabalho foi desenvolver uma escala válida e fidedigna para a avaliação de insegurança alimentar e nutricional especificamente em adolescentes. A versão inicial da escala foi composta por duas subescalas: percepção de insegurança alimentar e percepção de segurança nutricional. Os itens elaborados foram submetidos à análise de conteúdo por peritos em segurança alimentar e nutricional (n = 4) e à análise semântica por adolescentes selecionados por conveniência e oriundos da população alvo (n=20). Após ajustes, a versão final da escala foi aplicada junto a adolescentes escolares (n = 425) com idade entre 12 e 18 anos (m = 14,32±0,96; CV = 6,7%). Após realização de análise fatorial exploratória, um modelo de dois fatores foi o que se mostrou mais adequado. As subescalas avaliadas apresentaram valores modestos do coeficiente alfa (0,69 e 0,60, respectivamente). Consumo diário de frutas, verduras e refrigerantes se mostrou significativamente associado a escores mais elevados na escala de percepção de segurança alimentar e nutricional. Sugere-se a viabilidade de combinar itens com base no acesso a alimentos com outros relacionados a atitudes e práticas de alimentação saudável de modo a obter um retrato mais aproximado das necessidades dos adolescentes e melhor orientar políticas públicas.

Abstract This study aimed to develop a valid and reliable scale for assessing food and nutritional insecurity, specifically in adolescents. The initial version of the scale consisted of two subscales: perception of food insecurity and perception of nutritional security. The items were submitted to content analysis (n = 4) by a group of food and nutrition security experts, and semantic analysis (n = 20) by a group of adolescents conveniently sampled from the target population. After adjustments, the final version of the scale was applied to adolescent students (n = 425) aged 12 to 18 years (m = 14.32±0.96; CV = 6.7%). A two-factor model was the most appropriate after performing exploratory factor analysis. The subscales showed modest values of the alpha coefficient (0.69 and 0.60, respectively). Daily consumption of fruits, vegetables and soft drinks was significantly associated with higher scores in the food and nutrition security perception scale. Therefore, it is recommended to combine food access-based items with other aspects related to attitudes and behaviors towards healthy eating in order to achieve a more accurate picture of adolescent's needs and better guide public policies.

Crystal structure, vibrational frequencies and polarizability distribution in hydrogen-bonded salts of pyromellitic acid.

Structural features of moderate-to-strong O-H...O hydrogen bonds are related to the frequencies of O-H stretching vibrations and to the electric polarizability distribution in the donor and acceptor functional groups for crystals synthesized from the 1,2,4,5-benzenetetracarboxylic (pyromellitic) acid, namely: bis(3-aminopyridinium) dihydrogen pyromellitate tetrahydrate, (1); bis(3-carboxypyridinium) dihydrogen pyromellitate, (2); bis(3-carboxyphenylammonium) dihydrogen pyromellitate dihydrate, (3); and bis(4-carboxyphenylammonium) dihydrogen pyromellitate, (4). A combination of single-crystal X-ray diffraction, powder Raman spectroscopy and first-principle calculations in both crystalline and gaseous phases has shown that changes in the O-H...O hydrogen-bond geometry can be followed by changes in the corresponding spectral modes. Vibrational properties of moderate hydrogen bonds can be estimated from correlations based on statistical analysis of several compounds [Novak (1974). Struct. Bond. 18, 177-216]. However, frequencies related to very short O-H...O bonds can only be predicted by relationships built from a subset of structurally similar systems. Moreover, the way in which hydrogen bonds affect the polarizability of donor and acceptor groups depends on their strength. Moderate interactions enhance the polarizability and make it more anisotropic. Shorter hydrogen bonds may decrease the polarizability of a group as a consequence of the volume restraint implied by the neighbour molecule within a hydrogen-bonded aggregate. This is significant for evaluation of the electric susceptibility in crystals and, therefore, for estimation of refractive indices and birefringence.

Enhancing the solubility and permeability of the diuretic drug furosemide via multicomponent crystal forms.

Furosemide (FSM) is a biopharmaceutical classification system (BCS) class IV drug, being a potent loop diuretic used in the treatment of congestive heart failure and edema. Due to its low solubility and permeability, FSM is known for exhibiting poor oral bioavailability. In order to overcome or even minimize these undesirable biopharmaceutical attributes, in this work we have focused on the development of more soluble and permeable multicomponent solid forms of FSM. Using solvent evaporation as crystallization method, a salt and a cocrystal of FSM with imidazole (IMI) and 5-fluorocytosine (5FC) coformers, named FSM-IMI and FSM-5FC, respectively, were successfully prepared. A detailed structural study of these new solid forms was conducted using single and powder X-ray diffraction (SCXRD, PXRD), Fourier Transform Infrared (FT-IR) and proton Nuclear Magnetic Resonance (1H NMR) spectroscopy and thermal analysis (thermogravimetry, differential scanning calorimetry and hot-stage microscopy). Both FSM-IMI and FSM-5FC showed substantial enhancements in the solubility (up 118-fold), intrinsic dissolution (from 1.3 to 2.6-fold) and permeability (from 2.1 to 2.8-fold), when compared to the pure FSM. These results demonstrate the potential of these new solid forms to increase the limited bioavailability of FSM.

Comparison of automated and manual protocols for magnetic resonance imaging assessment of liver iron concentration.

OBJECTIVE: To compare automated and manual magnetic resonance imaging protocols for estimating liver iron concentrations at 1.5 T. MATERIALS AND METHODS: Magnetic resonance imaging examination of the liver was performed in 53 patients with clinically suspected hepatic iron overload and in 21 control subjects. Liver iron concentrations were then estimated by two examiners who were blinded to the groups. The examiners employed automated T2* and T1 mapping, as well as manual T2* and signal-intensity-ratio method. We analyzed accuracy by using ROC curves. Interobserver and intraobserver agreement were analyzed by calculating two-way intraclass correlation coefficients. RESULTS: The area under the ROC curve (to discriminate between patients and controls) was 0.912 for automated T2* mapping, 0.934 for the signal-intensity-ratio method, 0.908 for manual T2*, and 0.80 for T1 mapping, the last method differing significantly from the other three. The level of interobserver and intraobserver agreement was good (intraclass correlation coefficient, 0.938-0.998; p < 0.05). Correlations involving T1 mapping, although still significant, were lower. CONCLUSION: At 1.5 T, T2* mapping is a rapid tool that shows promise for the diagnosis of liver iron overload, whereas T1 mapping shows less accuracy. The performance of T1 mapping is poorer than is that of T2* methods.

OBJETIVO: Comparar protocolos automatizados e manuais de ressonância magnética para estimar a concentração hepática de ferro em 1,5 T. MATERIAIS E MÉTODOS: Foi realizada ressonância magnética hepática em 53 pacientes com suspeita de sobrecarga de ferro hepática e 21 controles, seguida da estimativa cega da concentração hepática de ferro por dois examinadores usando mapas automáticos T2* e T1, assim como o manual T2* e o método signal-intensity-ratio. O desempenho foi medido usando curvas ROC e a correlação interobservador e intraobservador usando o coeficiente de correlação intraclasse bidirecional. RESULTADOS: O desempenho da curva ROC separando pacientes e controles mostrou áreas sob a curva de 0,912 para o mapa automático T2*, 0,934 para o método signal-intensity-ratio, 0,908 para manual T2* e 0,80 para mapa T1 (este difere significativamente dos outros três métodos). Houve boa correlação interobservador e intraobservador (coeficiente de correlação intraclasse entre 0,938 e 0,998; p < 0,05). Correlações envolvendo o mapa T1, embora ainda significativas, foram menores. CONCLUSÃO: Em 1,5 T, o mapa T2* representa uma nova ferramenta rápida e promissora para avaliar o diagnóstico de sobrecarga de ferro hepática, enquanto o mapa T1 mostrou menor precisão. O desempenho do mapa T1 foi menor que o dos métodos T2*.

Comparison of automated and manual protocols for magnetic resonance imaging assessment of liver iron concentration / Comparação de protocolos automatizados e manuais de ressonância magnética para avaliação da concentração hepática de ferro

Abstract Objective: To compare automated and manual magnetic resonance imaging protocols for estimating liver iron concentrations at 1.5 T. Materials and Methods: Magnetic resonance imaging examination of the liver was performed in 53 patients with clinically suspected hepatic iron overload and in 21 control subjects. Liver iron concentrations were then estimated by two examiners who were blinded to the groups. The examiners employed automated T2* and T1 mapping, as well as manual T2* and signal-intensity-ratio method. We analyzed accuracy by using ROC curves. Interobserver and intraobserver agreement were analyzed by calculating two-way intraclass correlation coefficients. Results: The area under the ROC curve (to discriminate between patients and controls) was 0.912 for automated T2* mapping, 0.934 for the signal-intensity-ratio method, 0.908 for manual T2*, and 0.80 for T1 mapping, the last method differing significantly from the other three. The level of interobserver and intraobserver agreement was good (intraclass correlation coefficient, 0.938-0.998; p < 0.05). Correlations involving T1 mapping, although still significant, were lower. Conclusion: At 1.5 T, T2* mapping is a rapid tool that shows promise for the diagnosis of liver iron overload, whereas T1 mapping shows less accuracy. The performance of T1 mapping is poorer than is that of T2* methods.

Resumo Objetivo: Comparar protocolos automatizados e manuais de ressonância magnética para estimar a concentração hepática de ferro em 1,5 T. Materiais e Métodos: Foi realizada ressonância magnética hepática em 53 pacientes com suspeita de sobrecarga de ferro hepática e 21 controles, seguida da estimativa cega da concentração hepática de ferro por dois examinadores usando mapas automáticos T2* e T1, assim como o manual T2* e o método signal-intensity-ratio. O desempenho foi medido usando curvas ROC e a correlação interobservador e intraobservador usando o coeficiente de correlação intraclasse bidirecional. Resultados: O desempenho da curva ROC separando pacientes e controles mostrou áreas sob a curva de 0,912 para o mapa automático T2*, 0,934 para o método signal-intensity-ratio, 0,908 para manual T2* e 0,80 para mapa T1 (este difere significativamente dos outros três métodos). Houve boa correlação interobservador e intraobservador (coeficiente de correlação intraclasse entre 0,938 e 0,998; p < 0,05). Correlações envolvendo o mapa T1, embora ainda significativas, foram menores. Conclusão: Em 1,5 T, o mapa T2* representa uma nova ferramenta rápida e promissora para avaliar o diagnóstico de sobrecarga de ferro hepática, enquanto o mapa T1 mostrou menor precisão. O desempenho do mapa T1 foi menor que o dos métodos T2*.

X1INH, an improved next-generation affinity-optimized hydrazonic ligand, attenuates abnormal copper(I)/copper(II)-α-Syn interactions and affects protein aggregation in a cellular model of synucleinopathy.

Although normal aging presents an accumulation of copper and iron in the brain, this becomes more relevant in neurodegeneration. α-Synuclein (α-Syn) misfolding has long been linked with the development of Parkinson's disease (PD). Copper binding promotes aggregation of α-Syn, as well as generalized oxidative stress. In this sense, the use of therapies that target metal dyshomeostasis has been in focus in the past years. Metal-Protein Attenuating Compounds (MPACs) are moderate chelators that aim at disrupting specific, abnormal metal-protein interactions. Our research group has now established that N-acylhydrazones compose a set of truly encouraging MPACs for the bioinorganic management of metal-enhanced aggregopathies. In the present work, a novel ligand, namely 1-methyl-1H-imidazole-2-carboxaldehyde isonicotinoyl hydrazone (X1INH), is reported. We describe solution studies on the interaction and affinity of this compound for copper(ii) ions showing that a fine tuning of metal-affinity was achieved. A series of in vitro biophysical NMR experiments were performed in order to assess the X1INH ability to compete with α-Syn monomers for the binding of both copper(i) and copper(ii) ions, which are central in PD pathology. A preference for copper(i) has been observed. X1INH is less toxic to human neuroglioma (H4) cells in comparison to structure-related compounds. Finally, we show that treatment with X1INH results in a higher number of smaller, less compact inclusions in a well-established model of α-Syn aggregation. Thus, X1INH constitutes a promising MPAC for the treatment of Parkinson's disease.

Modified pyrazole platinum(II) complex can circumvent albumin and glutathione: Synthesis, structure and cytotoxic activity.

The synthesis and structural characterization of novel platinum complexes ([PtII(Pz)2Cl2] - C1, C2 and C3) featuring diphenyl-pyrazole derived ligands: para-fluorophenyl and para-substituted phenyl (CH3, F and Cl for L1, L2 and L3, respectively) were reported and it was also evaluated their potential antitumor activity. The elemental, molar conductivity and thermogravimetric analysis combined with FTIR, UV-vis, NMR and mass spectrometry are in agreement with the chemical structure indicated by single-crystal X-ray diffraction. The antiproliferative activities were assessed against tumor (B16F10 and 4T1) and non-tumor (BHK21) cell lines, and the cytotoxicity of the compounds was strongly increased after metal complexation displaying promising activity. It was also assessed the ability of extracellular bovine serum albumin (BSA) and glutathione (GSH) to decrease the cytotoxicity of the complexes against B16F10. It was highlighted that only the C3 activity was not disturbed in those conditions, being confirmed by flow cytometry using Anexin-V/PI to evaluate interferences in the apoptosis process, even it was not predicted by molecular docking simulations. The interaction of the synthesized compounds with calf-thymus DNA (ctDNA) and bovine serum albumin (BSA) was also investigated through spectrophotometric assays and molecular docking simulations, indicating that C1 and C2 presented better interaction with the biomacromolecules than the corresponding ligands. In addition, agarose gel electrophoresis with plasmid DNA revealed that C1-C3 are capable of interaction with DNA and modify its electrophoretic mobility.

Triethylphosphinegold(I) Complexes with Secnidazole-Derived Thiosemicarbazones: Cytotoxic Activity against HCT-116 Colorectal Cancer Cells under Hypoxia Conditions.

Triethylphosphinegold(I) complexes [Au(HL1)P(CH2CH3)3]PF6 (1), [Au(HL2)P(CH2CH3)3]PF6 (2), and [Au(HL3)P(CH2CH3)3]PF6 (3) were obtained with (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide (HL1), (E)-N-methyl-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)hydrazinecarbothioamide (HL2), and (E)-2-(1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ylidene)-N-phenylhydrazinecarbothioamide (HL3). All compounds were assayed for their cytotoxic activities against HCT-116 colorectal carcinoma cells under normoxia and hypoxia conditions and against nonmalignant HEK-293 human embryonic kidney cells under normoxia conditions. The thiosemicarbazone ligands HL1-HL3 were inactive against HCT-116 cells under hypoxia but while HL3 was inactive, HL1 and HL2 proved to be cytotoxic to both cell lineages under normoxia conditions. Complexes (1-3) and the triethylphosphinegod(I) precursor proved to be active against both cell lineages in normoxia as well as in hypoxia. While 1 and 3 revealed to be active against HEK-293 and HCT-116 cells, being approximately as active against HCT-116 cells in normoxia as under hypoxia, complex (2) proved to be more active against HCT-116 cells under hypoxia than under normoxia conditions, and more active against HCT-116 cells than against the nonmalignant HEK-293 cells, with the selectivity index, calculated as SI = IC50HEK-293/IC50HCT-116hypoxia, equal to 3.7, similar to the value obtained for the control drug tirapazamine (tirapazamine (TPZ), SI = 4). Although the compounds showed distinct cytotoxic activities, the electrochemical behaviors of HL1-HL3 were very similar, as were the behaviors of complexes (1-3). Complex (2) deserves special interest since it was significantly more active under hypoxia than under normoxia conditions. Hence, in this case, selective reduction of the nitro group in a low oxygen pressure environment, resulting in toxic reactive oxygen species (ROS) and damage to DNA or other biomolecules, might operate, while for the remaining compounds, other modes of action probably occur.

O papel da ressonância magnética na distinção das gestações intersticial, cornual e angular / The role of magnetic resonance imaging in distinguishing interstitial, cornual and angular pregnancies

Apesar da melhora no diagnóstico e tratamento, a gravidez ectópica ainda é a principal causa de mortalidade materna no primeiro trimestre da gravidez. Formas raras podem apresentar um desafio diagnóstico e, sem um diagnóstico adequado, a incidência de complicações e a mortalidade materna estão relacionadas a aumento de seus índices. Os termos "gravidez cornual" e "gravidez intersticial" têm sido utilizados de forma inconsistente na literatura, sendo frequentemente usados como sinônimos do termo "gravidez angular". Uma distinção estrita entre essas entidades pode ter implicações clínicas importantes, porque o curso natural, a propedêutica e os resultados diferem entre eles. A ressonância magnética não é o padrão-ouro para o diagnóstico de gravidez ectópica, no entanto possui relevância significativa no diagnóstico de possíveis complicações decorrentes dessa afecção. Nesse contexto, esta revisão aborda a importância da ressonância magnética na distinção dos tipos de gravidez mencionados, ilustrados por meio de casos do nosso serviço.(AU)

Despite the improvement in diagnostics and treatment, ectopic pregnancies are still the main cause of maternal mortality in the first trimester of pregnancy. Rare forms may present a diagnostic challenge and without adequate diagnosis, the incidence of complications and maternal mortality is greatly increased. The terms "cornual pregnancy" and "interstitial pregnancy" have been used inconsistently in the literature, frequently been used as synonyms and even used interchangeably with the term "angular pregnancy". A strict distinction among these entities can have important clinical implications because the natural course, management and outcomes differ among them. Magnetic resonance imaging is not the gold standard for the diagnosis of ectopic pregnancy, however, it can be useful in the diagnosis of complicated presentations of such ailment. In this context, this review highlights the importance of MRI in distinguishing the aforementioned types of pregnancies, illustrated with few cases from our service.(AU)