Topliss method in the optimization of salicylic acid derivatives as potential antimycobacterial agents

The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p-chloro, p-methoxy, and m-chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p-aminosalicylic acid. Several physicochemical descriptors (including Hammett`s sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol-L and -B-4 and molecular volume) were considered to elucidate structure-activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi-empirical method. Among the new derivatives, m-chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p-aminosalicylic acid analogs.

Box-Behnken design for the optimization of an enantioselective method for the simultaneous analysis of propranolol and 4-hydroxypropranolol by CE

An experimental design optimization (Box-Behnken design, BBD) was used to develop a CE method for the simultaneous resolution of propranolol (Prop) and 4-hydroxypropranolol enantiomers and acetaminophen (internal standard). The method was optimized using an uncoated fused silica capillary, carboxymethyl-beta-cyclodextrin (CM-beta-CD) as chiral selector and triethylamine/phosphoric acid buffer in alkaline conditions. A BBD for four factors was selected to observe the effects of buffer electrolyte concentration, pH, CM-beta-CD concentration and voltage on separation responses. Each factor was studied at three levels: high, central and low, and three center points were added. The buffer electrolyte concentration ranged from 25 to 75 mM, the pH ranged from 8 to 9, the CM-beta-CD concentration ranged from 3.5 to 4.5%w/v, and the applied run voltage ranged from 14 to 20 W. The responses evaluated were resolution and migration time for the last peak. The obtained responses were processed by Minitab (R) to evaluate the significance of the effects and to find the optimum analysis conditions. The best results were obtained using 4%w/v CM-beta-CD in 25 mM triethylamine/H(3)PO(4) buffer at pH 9 as running electrolyte and 17 kV of voltage. Resolution values of 1.98 and 1.95 were obtained for Prop and 4-hydroxypropranolol enantiomers, respectively. The total analysis time was around of 15 min. The BBD showed to be an adequate design for the development of a CE method, resulting in a rapid and efficient optimization of the pH and concentration of the buffer, cyclodextrin concentration and applied voltage.

In Vivo Evaluation of the Photoprotective Efficacy of O-1/W/O-2 Multiple Emulsions with Andiroba Oil (Carapa guianensis)

Stable multiple emulsions containing andiroba oil and sunscreen have been formulated. These were prepared using the two-step procedure. The formulations were characterized and their stability over the time was evaluated by centrifugation, macroscopic, and microscopic analyses, and rheological measurements. The photoprotective efficacy of the O/W and O1/W/O2 containing or not andiroba oil was evaluated by in vivo sun protection factor determination according to the FDA method. The formulations exhibited good stability during 30 days after preparation at different temperatures. These presented pseudoplastic flow behaviour and thixotropy. The increase of in vivo SPF value was not observed when andiroba oil was incorporated into emulsions containing ethylhexyl methoxycinnamate. These multiple emulsions can be utilized as an interesting topical vehicle.

W/O/W multiple emulsions obtained by one-step emulsification method and evaluation of the involved variables

The effects of some composition variables on the development of multiple emulsions by one-step method were evaluated and their morphology characterized. The formulations that remained stable during the period of the test were submitted to centrifugation and thermal stress tests. The stability and the morphology of multiple droplets were affected not only by the type and concentration of the surfactants employed, but also by the water/oil ratios used. The results suggest that the formation of multiple droplets could involve a combination of transitional and catastrophic phase inversions. The results provide improved knowledge about the one-step emulsification method, a simplified process to prepare multiple emulsions when compared to the two-steps method.

Relationship between Rheological Properties and One-Step W/O/W Multiple Emulsion Formation

Formation of a normal (not temporary) W/O/W multiple emulsion via the one-step method as a result of the simultaneous occurrence of catastrophic and transitional phase inversion processes has been recently reported. Critical features of this process include the emulsification temperature (corresponding to the ultralow surface tension point), the use of a specific nonionic surfactant blend and the surfactant blend/oil phase ratio, and the addition of the surfactant blend to the oil phase. The purpose of this study was to investigate physicochemical properties in an effort to gain a mechanistic understanding of the formation of these emulsions. Bulk, surface, and interfacial theological properties of adsorbed nonionic surfactant (CremophorRH40 and Span80) films were investigated under conditions known to affect W/O/W emulsion formation. Bulk viscosity results demonstrated that CremophorRH40 has a higher mobility in oil compared than in water, explaining the significance of the solvent phase. In addition, the bulk viscosity profile of aqueous solutions containing CremophorRH40 indicated a phase transition at around 78 +/- 2 degrees C, which is in agreement with cubic phase formation in the Winsor III region. The similarity in the interfacial elasticity values of CremophorRH40 and Span80 indicated that canola oil has a major effect on surface activity, showing the significance of vegetable oil. The highest interfacial shear elasticity and viscosity were observed when both surfactants were added to the oil phase, indicating the importance of the microstructural arrangement. CremophorRH40/Span80 complexes tended to desorb from the solution/solution interface with increasing temperature, indicating surfactant phase formation as is theoretically predicted in the Winsor III region. Together these interfacial and bulk rheology data demonstrate that one-step W/O/W emulsions form as a result of the simultaneous occurrence of phase-transition processes in the Winsor III region and explain the critical formulation and processing parameters necessary to achieve the formation of these normal W/O/W emulsions.

Exploratory Approach to the use of Techniques of Regression Analysis and Pooled Analysis in Studies of Consumer Behavior

This paper is part of a large study to assess the adequacy of the use of multivariate statistical techniques in theses and dissertations of some higher education institutions in the area of marketing with theme of consumer behavior from 1997 to 2006. The regression and conjoint analysis are focused on in this paper, two techniques with great potential of use in marketing studies. The objective of this study was to analyze whether the employement of these techniques suits the needs of the research problem presented in as well as to evaluate the level of success in meeting their premisses. Overall, the results suggest the need for more involvement of researchers in the verification of all the theoretical precepts of application of the techniques classified in the category of investigation of dependence among variables.

A note on the multiple partners assignment game

In the assignment game of Shapley and Shubik [Shapley, L.S., Shubik, M., 1972. The assignment game. I. The core, International journal of Game Theory 1, 11-130] agents are allowed to form one partnership at most. That paper proves that, in the context of firms and workers, given two stable payoffs for the firms there is a stable payoff which gives each firm the larger of the two amounts and also one which gives each of them the smaller amount. Analogous result applies to the workers. Sotomayor [Sotomayor, M., 1992. The multiple partners game. In: Majumdar, M. (Ed.), Dynamics and Equilibrium: Essays in Honor to D. Gale. Mcmillian, pp. 322-336] extends this analysis to the case where both types of agents may form more than one partnership and an agent`s payoff is multi-dimensional. Instead, this note concentrates in the total payoff of the agents. It is then proved the rather unexpected result that again the maximum of any pair of stable payoffs for the firms is stable but the minimum need not be, even if we restrict the multiplicity of partnerships to one of the sides. (C) 2009 Elsevier B.V. All rights reserved.

Adjusting prices in the multiple-partners assignment game

Starting with an initial price vector, prices are adjusted in order to eliminate the excess demand and at the same time to keep the transfers to the sellers as low as possible. In each step of the auction, to which set of sellers should those transfers be made is the key issue in the description of the algorithm. We assume additively separable utilities and introduce a novel distinction by considering multiple sellers owing multiple identical objects and multiple buyers with an exogenously defined quota, consuming more than one object but at most one unit of a seller`s good and having multi-dimensional payoffs. This distinction induces a necessarily more complicated construction of the over-demanded sets than the constructions of these sets for the other assignment games. For this approach, our mechanism yields the buyer-optimal competitive equilibrium payoff, which equals the buyer-optimal stable payoff. The symmetry of the model allows to getting the seller-optimal stable payoff and the seller-optimal competitive equilibrium payoff can then be also derived.

Stakeholders Theory and Theory of the Firm: a study on the hierarchy of objective-functions in Brazilian companies

Discussion opposing the Theory of the Firm to the Theory of Stakeholders are contemporaneous and polemical. One focal point of such debates refers to which objective-function companies, should choose, whether that of the shareholders or that of the stakeholders, and whether it is possible to opt for both simultaneously. Several empirical studies. have attempted-to test a possible correlation between both functions, and there has not been any consensus-so far. The objective of the present research is to examine a gap in such discussions: is there (or not) a subordination of the stakeholders` objective-function to that of the shareholders? The research is empirical,and analytical and employs quantitative methods. Hypotheses were tested and data analyzed by using non-parametrical (chi-square test) and parametrical procedures (frequency. correlation `coefficient). Secondary data was collected from he Economitica database and from the Brazilian Institute of Social and-Economic Analyses (IBASE) website, relative to public companies that have published their Social Balance Statements following the IBASE model from 1999 to 2006, whose sample amounted to 65 companies; In order to assess the objective-function of shareholders a proxy was created based on the following three indices: ROE (return on equity), EnterpriseValue and Tobin`s Q. In order to assess the objective-function of stakeholders a proxy was created by employing the following IBASE social balance indices: internal ones (ISI), external ones (ISE), and environmental ones (IAM). The results have shown no evidence of subordination of stakeholders` objective-function to that of the shareholders in analyzed companies, negating initial expectations and calling for deeper investigation of results. Its main conclusion, which states that the attempted subordination does not take place, is limited to the sample herein investigated and calls for ongoing research aiming at improvements which may lead to sample enlargement and, as a consequence, may make feasible the application of other statistical techniques which may yield a more thorough, analysis of the studied phenomehon.

Homicide mortality, socioeconomic development, and police violence in the city of Sao Paulo, Brazil

Objective. To analyze the association between police violence and homicide mortality rates taking into consideration the effect of contextual variables. Methods. This was an environmental, cross-sectional study that included the 96 census districts in the City of Sao Paulo. The association between the variables was analyzed using Spearman`s rank correlation and simple and multiple regression analysis. Results. Univariate analysis revealed a strong and significant association between homicide mortality coefficients and all the indicators of socioeconomic development and police violence. After controlling for potential confounding factors, the association between police violence and homicide mortality coefficients remained strong and significant. This significance was lost only after control for the size of the resident population. Conclusion. The results indicate that police action that violates basic human rights is not the right answer to urban violence. The combination of homicides from interpersonal violence and deaths from police violence results in negative socialization and promotes further violence.

Chronic Recurrent Multifocal Osteomyelitis Primarily Affecting the Spine Treated With Anti-TNF Therapy

Study Design. A case report describing chronic recurrent multifocal osteomyelitis (CRMO) with initial presentation limited to spine, successfully treated by anti-TNF-alpha therapy after failure of conventional treatment methods. Objective. To describe an unusual manifestation and treatment of a rare disease. Summary of Background Data. CRMO is a rare inflammatory bone disease that should be differentiated from bacterial osteomyelitis. Rarely, it can affect the spine and in this case the most important differential diagnosis is infectious spondylodiscitis. The disease has an unpredictable course with exacerbations and spontaneous remissions. Although the majority of cases remit spontaneously (or after the use of nonsteroidal anti-inflammatory drugs [NSAIDs]), some progressive and resistant cases have been reported. Methods. We describe a case of CRMO with an unusual clinical presentation emphasizing the importance of this finding as a differential diagnosis of spondylodiscitis and comment on the available treatment alternatives. Results. A 17-year-old man presented with debilitating dorsal spine pain. Magnetic resonance imaging of the spine revealed bone lesions at multiple vertebral levels. After failure of antibiotic treatment, the diagnosis of CRMO was suggested. An initial good response to NSAIDs was followed by a recurrent course and involvement of peripheral joints besides the use of corticosteroids and other drugs. The introduction of infliximab was followed by complete remission of the disease. Conclusion. Our observation highlights the need of awareness for the differential diagnosis in suspected cases of osteomyelitis not responding to antibiotics. Anti-TNF-alpha agents should be considered in CRMO refractory cases.

High Penetrance of Pheochromocytoma Associated with the Novel C634Y/Y791F Double Germline Mutation in the RET Protooncogene

Context: Previous studies have shown that double RET mutations may be associated with unusual multiple endocrine neoplasia type 2 (MEN 2) phenotypes. Objective: Our objective was to report the clinical features of patients harboring a previously unreported double mutation of the RET gene and to characterize this mutation in vitro. Patients: Sixteen patients from four unrelated families and harboring the C634Y/Y791F double RET germline mutation were included in the study. Results: Large pheochromocytomas measuring 6.0-14 cm and weighing upto 640 g were identified in the four index cases. Three of the four tumors were bilateral. High penetrance of pheochromocytoma was also seen in the C634Y/Y791F-mutation-positive relatives (seven of nine, 77.7%). Of these, two cases had bilateral tumors, one presented with multifocal tumors, two cases had large tumors (>5 cm), and one case, which was diagnosed with a large (5.5 x 4.5 x 4.0 cm) pheochromocytoma, reported early onset of symptoms of the disease (14 yr old). The overall penetrance of pheochromocytoma was 84.6% (11 of 13). Development of medullary thyroid carcinoma in our patients seemed similar to that observed in patients with codon 634 mutations. Haplotype analysis demonstrated that the mutation did not arise from a common ancestor. In vitro studies showed the double C634Y/Y791F RET receptor was significantly more phosphorylated than either activated wild-type receptor or single C634Y and Y791F RET mutants. Conclusions: Our data suggest that the natural history of the novel C634Y/Y791F double mutation carries a codon 634-like pattern of medullary thyroid carcinoma development, is associated with increased susceptibility to unusually large bilateral pheochromocytomas, and is likely more biologically active than each individual mutation. (J Clin Endocrinol Metab 95: 1318-1327, 2010)

Extraadrenal 21-Hydroxylation by CYP2C19 and CYP3A4: Effect on 21-Hydroxylase Deficiency

Context: 21-Hydroxylase deficiency (21OHD) is caused by CYP21A2 gene mutations disrupting the adrenal 21-hydroxylase, P450c21. CYP21A2 mutations generally correlate well with the 21OHD phenotype, but some children with severe CYP21A2 mutations have residual 21-hydroxylase activity. Some hepatic P450 enzymes can 21-hydroxylate progesterone, but their physiological relevance in modifying 21OHD is not known. Objective: Wedetermined the ability of CYP2C19 and CYP3A4 to 21-hydroxylate progesterone and 17-hydroxyprogesterone (17OHP), determined the impact of the common P450 oxidoreductase (POR) variant A503V on these activities, and examined correlations between CYP2C19 variants and phenotype in patients with 21OHD. Methods: Bacterially expressed, N-terminally modified, C-His-tagged human P450c21, CYP2C19, and CYP3A4 were combined with bacterially expressed wild-type and A503V POR. The 21-hydroxylation of radiolabeled progesterone and 17OHP was assessed, and the Michaelis constant (Km) and maximum velocity (Vmax) of the reactions were measured. CYP2C19 was genotyped in 21OHD patients with genotypes predicting severe congenital adrenal hyperplasia. Results: Compared to P450c21, the Vmax/Km for 21-hydroxylation of progesterone by CYP2C19 and CYP3A4 were 17 and 10%, respectively. With both forms of POR, the Km for P450c21 was approximately 2.6 mu M, the Km for CYP2C19 was approximately 11 mu M, and the Km for CYP3A4 was approximately 110 mu M. Neither CYP2C19 nor CYP3A4 could 21-hydroxylate 17OHP. The CYP2C19 ultrametabolizer allele CYP2C19* 17 was homozygous in one of five patients with a 21OHD phenotype that was milder than predicted by the CYP21A2 genotype. Conclusions: CYP2C19 and CYP3A4 can 21-hydroxylate progesterone but not 17OHP, possibly ameliorating mineralocorticoid deficiency, but not glucocorticoid deficiency. Multiple enzymes probably contribute to extraadrenal 21-hydroxylation. (J Clin Endocrinol Metab 94: 89-95, 2009)

Three-dimensional electrical impedance, tomography: A topology optimization approach

Electrical impedance tomography is a technique to estimate the impedance distribution within a domain, based on measurements on its boundary. In other words, given the mathematical model of the domain, its geometry and boundary conditions, a nonlinear inverse problem of estimating the electric impedance distribution can be solved. Several impedance estimation algorithms have been proposed to solve this problem. In this paper, we present a three-dimensional algorithm, based on the topology optimization method, as an alternative. A sequence of linear programming problems, allowing for constraints, is solved utilizing this method. In each iteration, the finite element method provides the electric potential field within the model of the domain. An electrode model is also proposed (thus, increasing the accuracy of the finite element results). The algorithm is tested using numerically simulated data and also experimental data, and absolute resistivity values are obtained. These results, corresponding to phantoms with two different conductive materials, exhibit relatively well-defined boundaries between them, and show that this is a practical and potentially useful technique to be applied to monitor lung aeration, including the possibility of imaging a pneumothorax.

Risk Profiles and Penetrance Estimations in Multiple Endocrine Neoplasia Type 2A Caused by Germline RET Mutations Located in Exon 10

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609-620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected. Hum Mutat 32:51-58, 2011. (C) 2010 Wiley-Liss, Inc.