3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r (2) ranging from 0.83 to 0.92 and q (2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

Rational Design and 3D-Pharmacophore Mapping of 5 `-Thiourea-Substituted alpha-Thymidine Analogues as Mycobacterial TMPK Inhibitors

Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5`-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5`-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.

Process Capability Indexes Determination on Tabletting Performance during the Process Validation for Metamizol Tablets

The aim of the present study was to provide a numerical measure, through the process capability indexes (PCIs), C(p) and C(pk), on whether or not the manufacturing process can be considered capable of producing metamizol (500 mg) tablets. They were also used as statistical tool in order to prove the consistency of the tabletting process, making sure that the tablet weight and the content uniformity of metamizol are able to comply with the preset requirements. Besides that, the ANOVA, the t-test and the test for equal variances were applied to this study, allowing additional knowledge of the tabletting phase. Therefore, the proposed statistical approach intended to assure more safety, precision and accuracy on the process validation analysis.

Structured lipids obtained by chemical interesterification of olive oil and palm stearin

Interesterification of palm stearin (PS) with liquid vegetable oils could yield a good solid fat stock that may impart desirable physical properties, because PS is a useful source of vegetable hard fat, providing beta` stable solid fats Dietary ingestion of olive oil (OO) has been reported to have physiological benefits such as lowering serum cholesterol levels Fat blends, formulated by binary blends of palm stearin and olive oil in different ratios, were subjected to chemical interesterification with sodium methoxide The original and interesterified blends were examined for fatty acid and triacylglycerol composition, melting point, solid fat content (SFC) and consistency. Interestenfication caused rearrangement of triacylglycerol species, reduction of trisaturated and triunsaturated triacylglycerols content and increase in diunsaturated-monosaturated triacylglycerols of all blends, resulting in lowering of melting point and solid fat content The incorporation of OO to PS reduced consistency, producing more plastic blends The mixture and chemical interesterification allowed obtaining fats with various degrees of plasticity, increasing the possibilities for the commercial use of palm stearin and olive oil (C) 2009 Elsevier Ltd All rights reserved

Effects of chemical interesterification on physicochemical properties of blends of palm stearin and palm olein

Chemical interesterification is an important technological option for the production of fats targeting commercial applications. Fat blends, formulated by binary blends of palm stearin and palm olein in different ratios, were subjected to chemical interesterification. The following determinations, before and after the interesterification reactions, were done: fatty acid composition, softening point, melting point, solid fat content and consistency. For the analytical responses a multiple regression statistical model was applied. This study has shown that blending and chemical interesterifications are an effective way to modify the physical and chemical properties of palm stearin, palm olein and their blends. The mixture and chemical interesterification allowed obtaining fats with various degrees of plasticity, increasing the possibilities for the commercial use of palm stearin and palm olein. (C) 2009 Elsevier Ltd. All rights reserved.

The effects of enzymatic interesterification on the physical-chemical properties of blends of lard and soybean oil

The main goal of the present research effort was to evaluate the physical-chemical properties of blends of lard and soybean oil following enzymatic interesterification catalyzed by an immobilized lipase from Thermomyces lanuginosa (Lipozyme (TM) TL IM). Lipase-catalyzed interesterification produced new tri-acylglycerols that changed the physical-chemical properties of the fat blends under study. Solid fat content (31.3 vs 31.5 g/100 g), consistency (104.7 vs 167.6 kPa), crystallized area (0.6 vs 11.8) and softening point (31.8 vs 32.2 degrees C) of lard increased after interesterification, and this was mostly due to the increase of SSS (saturated) + SSU (disaturated-monounsaturated) triacylglycerols. These contents (SSU + SSS) increased in lard after interesterification from 42.9 to 46.7 g/100 g. The interesterified blends exhibited lower values for the physical properties when compared with their counterparts before enzymatic interesterification. The interesterification of blends of lard with soybean oil increased the amounts of UUU (triunsaturated) and SSS triacylglycerols and reduced the amounts of UUS (diunsaturated-monosaturated) triacylglycerols. The interesterified blends of lard and soybean oil demonstrated physical properties and chemical composition similar to human milk fat and they could be used for the production of a human milk fat substitute. (C) 2009 Elsevier Ltd. All rights reserved.

EFFECT OF CHEMICAL INTERESTERIFICATION ON PHYSICOCHEMICAL PROPERTIES AND INDUSTRIAL APPLICATIONS OF CANOLA OIL AND FULLY HYDROGENATED COTTONSEED OIL BLENDS

Blends of canola oil (CO) and fully hydrogenated cottonseed oil (FHCSO), with 20, 25, 30, 35 and 40% FHCSO (w/w) were interesterified under the following conditions: 0.4% sodium methoxide, 500 rpm stirring, 100C, 20 min. The original and interesterified blends were examined for triacylglycerol composition, melting point, solid fat content (SFC) and consistency. Interesterification caused considerable rearrangement of triacylglycerol species, reduction of trisaturated triacylglycerol content and increase in disaturated-monounsaturated and monosaturated-diunsaturated triacylglycerols in all blends, resulting in lowering of respective melting points. The interesterified blends showed reduced SFC at all temperatures and more linear melting profiles if compared with the original blends. Consistency, expressed as yield value, significantly decreased after the reaction. Iso-solid curves indicated eutectic interactions for the original blends, which were eliminated after randomization. The 80:20, 75:25, 70:30 and 65:35 (w/w) CO: FHCSO interesterified blends showed characteristics which are appropriate for their application as soft margarines, spreads, fat for bakery/all-purpose shortenings, and icing shortenings, respectively. PRACTICAL APPLICATIONS Recently, a number of studies have suggested a direct relationship between trans isomers and increased risk of vascular disease. In response, many health organizations have recommended reducing consumption of foods containing trans fatty acids. In this connection, chemical interesterification has proven the main alternative for obtaining plastic fats that have low trans isomer content or are even trans isomer free. This work proposes to evaluate the chemical interesterification of binary blends of canola oil and fully hydrogenated cottonseed oil and the specific potential application of these interesterified blends in food products.

Growth and acidification performance of probiotics in pure culture and co-culture with Streptococcus thermophilus: The effect of inulin

Inulin was used as a prebiotic to improve the quality and consistency of skim milk fermented by co-cultures and pure Cultures of Lactobacillus acidophilus, Lactobacillus rhamnosus, Lactobacillus bulgaricus and Bifidobacterium lactis with Streptococcus thermophilus. We compared, either in the presence or absence of 4 g inulin/100 g, the results of the main kinetic parameters, specifically the generation time (t(g)), the maximum acidification rate (V(max)). and the times to reach V(max) (t(max)), to attain pH 5.0 (t(pH5.0)) and to complete the fermentation (t(pH4.5)). Post-acidification, lactic acid formation and cell counts were also determined and compared, either 1 day after the fermentation was complete or after 7 day storage at 4 degrees C. In general, inulin addition to the milk increased in co-cultures V(max), decreased t(max), t(g) and t(pH4.5), favored post-acidification, exerted a bifidogenic effect, and preserved almost intact cell viability during storage. In addition, S. thermophilus was shown to stimulate the metabolism of the other lactic bacteria. Contrary to co-cultures, most of the effects in pure Cultures were not statistically significant. The most important aspect of this paper is the use of the generation time as a toot to investigate the microbial response to inulin addition. (c) 2009 Elsevier Ltd. All rights reserved.

Zero trans fats from soybean oil and fully hydrogenated soybean oil: Physico-chemical properties and food applications

Blends of soybean oil (50) and fully hydrogenated soybean oil (FHSBO), with 10%, 20%, 30%, 40% and 50% FHSBO (w/w) content were interesterified under the following conditions: 0.4% sodium methoxide, 500 rpm stirring, 100 degrees C, 20 min. The original and interesterified blends were examined for triacylglycerol composition, melting point, solid fat content (SFC) and consistency. Interesterification caused considerable rearrangement of triacylglycerol species, reduction of trisaturated triacylglycerol content and increase in monounsaturated and diunsaturated triacylglycerols, resulting in lowering of respective melting points. The interesterified blends displayed reduced SFC at all temperatures and more linear melting profiles as compared with the original blends. Yield values showed increased plasticity in the blends after the reaction. Isosolid diagrams before and after the reaction showed no eutectic interactions. The 90:10, 80:20, 70:30 and 60:40 interesterified SO:FHSBO blends displayed characteristics suited to application, respectively, as liquid shortening, table margarine, baking/confectionery fat and all-purpose shortenings/biscuit-filing base. (C) 2009 Elsevier Ltd. All rights reserved.

Effect of inulin on growth and acidification performance of different probiotic bacteria in co-cultures and mixed culture with Streptococcus thermophilus

Inulin was used as a prebiotic to improve the quality and consistency of skim milk fermented by Lactobacillus acidophilus (La), Lactobacillus rhamnosus (Lr), Lactobacillus bulgaricus (Lb) and Bifidobacterium lactis (BI) with Streptococcus thermophilus (St), either in binary co-cultures or in cocktail containing all microorganisms. We compared, either in the presence of 40 mg inulin g(-1) or not, the results of the maximum acidification rate (V(max)) and the times to reach it (t(max)), to reach pH 5.0 (t(PH5.0)) and to complete the fermentation (t(f)). Post-acidification, lactic acid formation and cell counts were also compared after either 1 day (D1) or 7 days of storage at 4 degrees C (N). In co-culture, inulin addition to the milk increased V(max), decreased t(max) and t(f), favored post-acidification and exerted a bifidogenic effect. S. thermophilus proved to stimulate the metabolism of the other lactic bacteria and enhanced the product features. After D7, a significant prebiotic effect of inulin was observed in all co-cultures. Either after D1 or D7, the enumerations of Lr and BI in mixed culture markedly decreased compared to their respective co-cultures because of greater competition for the same substrates. (C) 2008 Elsevier Ltd. All rights reserved.

Is your vision consistent? A method for checking, based on scenario concepts

Common sense tells us that the future is an essential element in any strategy. In addition, there is a good deal of literature on scenario planning, which is an important tool in considering the future in terms of strategy. However, in many organizations there is serious resistance to the development of scenarios, and they are not broadly implemented by companies. But even organizations that do not rely heavily on the development of scenarios do, in fact, construct visions to guide their strategies. But it might be asked, what happens when this vision is not consistent with the future? To address this problem, the present article proposes a method for checking the content and consistency of an organization`s vision of the future, no matter how it was conceived. The proposed method is grounded on theoretical concepts from the field of future studies, which are described in this article. This study was motivated by the search for developing new ways of improving and using scenario techniques as a method for making strategic decisions. The method was then tested on a company in the field of information technology in order to check its operational feasibility. The test showed that the proposed method is, in fact, operationally feasible and was capable of analyzing the vision of the company being studied, indicating both its shortcomings and points of inconsistency. (C) 2007 Elsevier Ltd. All rights reserved.

Influence of ovariectomy and masticatory hypofunction on mandibular bone remodeling

Introduction: This study was designed to examine the effect of masticatory hypofunction and estrogen deficiency on mandible bone mass and compare this site with spine and femoral bone. Methods: Twenty-four rats were ovariectomized (OVX) or Sham-operated (Sham) and analyzed after feeding with hard diet (Hard) or soft diet (Soft). They were divided into four groups: (GI)Sham-Hard; (GII)OVX-Hard; (GIII)Sham-Soft and (GIV)OVX-Soft. Bone mineral density (BMD) was measured in the spine and femur in the baseline and at the end of the study, and Delta BMD (final BMD - baseline BMD) was calculated. In mandible bone, BMD and histomorphometry were analyzed at the end of the experiment. Results: Sham rats showed higher spine (GI: 13.5%vs GII: 0.74%, P < 0.01; GIII: 10.67%vs GIV: -4.36%, P < 0.001) and femur Delta BMD (GI: 14.43%vs GII: 4.42%, P < 0.01; GIII: 10.58%vs GIV: 0.49%, P < 0.001) than OVX, but no difference was observed in mandible BMD among these groups (P > 0.05). Soft-diet groups showed decreased mandible BMD compared with hard-diet groups (GIV vs GII, P < 0.01; GIII vs GI, P < 0.01). Similarly, mandibular condyle histomorphometry showed that soft-diet groups presented a significant decrease in trabecular thickness and volume (GIV vs GII, P < 0.05; GIII vs GI, P < 0.01) compared with hard diet. Conclusion: Our results suggest that mandibular bone loss resulted from decreased of mechanical loading during mastication, and was not affect by estrogen depletion.

Portuguese version of the Delirium Rating Scale-Revised-98: reliability and validity

Objective To assess the validity and the reliability of the Portuguese version of the Delirium Rating Scale-Revised-98 (DRS-R-98). Methods The scale was translated into Portuguese and back-translated into English. After assessing its face validity, five diagnostic groups (n = 64; delirium, depression, dementia, schizophrenia and others) were evaluated by two independent researchers blinded to the diagnosis. Diagnosis and severity of delirium as measured by the DRS-R-98 were compared to clinical diagnosis, Mini-Mental State Exam, Confusion Assessment Method, and Clinical Global Impressions scale (CGI). Results Mean and rnedian DRS-R-98 total scores significantly distinguished delirium from the other groups (p < 0.001). Inter-rater reliability (ICC between 0.9 and 1) and internal consistency (alpha = 0.91) were very high. DRS-R-98 severity scores correlated highly with the CGI. Mean DRS-R-98 severity scores during delirium differed significantly (p < 0.01) from the post-treatment values. The area under the curve established by ROC analysis was 0.99 and using the cut-off Value of 20 the scale showed sensitivity and specificity of 92.6% and 94.6%, respectively. Conclusion The Portuguese version of the DRS-R-98 is a valid and reliable measure of delirium that distinguishes delirium from other disorders and is sensitive to change in delirium severity, which may be of great value for longitudinal studies. Copyright (c) 2007 John Wiley & Sons, Ltd.

Validation of ASHA FACS-Functional Assessment of Communication Skills for Alzheimer Disease Population

This study vas aimed to validate the American Speech-Language-Hearing Association Functional Assessment Of Communication Skills (ASHA FACS) for a Brazilian population. The scale was translated and adapted into Portuguese. Thirty-two patients with mild Alzheimer disease (AD). 25 patients with moderate AD. and 51 elderly without dementia were examined with Mini Mental State Examination, Geriatric Depression Scale. and Alzheimer Disease Assessment Scale-Cognitive subscale (ADAS-cog). The ASHA FACS was answered by their relative/caregiver. The scale`s internal consistency. its inter-examiner and intra-examiner`s reproducibility. and scale`s criterion validity were researched by correlation with ADAS-cog,. The sensitivity and specificity Were also researched. Statistical analyses indicated that the ASHA FACS has excellent internal consistency (Cronbach alpha = 0.955), test-retest reliability (interclass correlation coefficient = 0.995; P < 0.001). and inter-examiners (interclass correlation coefficient = 0.998: P < 0.001). It showed excellent criterion validity when correlated with ADAS-cog,. The ASHA FACS scale showed good sensitivity (75.0%) and specificity (82.4%) values once it is an ecologic and broad evaluation. The ASHA FACS Portuguese version is a valid and reliable instrument to verify communication alterations in AD patients and fills an important gap of efficiency indicators for speech language therapy in our country.

Applicability of the university of pennsylvania smell identification test (SIT) in brazilians: pilot study

The University of Pennsylvania Smell Identification Test (SIT) is the most cited olfactory test in the literature because it is easy to perform and there is high test-retest reliability. There were no standardized olfaction values in a normal Brazilian population. Aim: To measure the SIT score in a group of Brazilians, and to assess the level of difficulty when implementing the test. Study design: A cross-sectional study. Materials and Methods: The SIT was applied in 25 Brazilian volunteers of various income levels who presented no olfactory complaints. Following the test, subjects answered a questionnaire with a visual analog scale (VAS) for the level of difficulty. Results: The mean in the sample of Brazilians was 32.5 (SD: 3.48) our of 40; this is below what is considered normal for US citizens. The level of difficulty was on average 26 mm (SD: 24.68) in the VAS, but it trended towards easy; 4(16%) participants did not recognize some of the odors under `alternatives`. Conclusion: In this pilot study, there was evidence of good test applicability; the score of the sample of Brazilians was just below normosmia. Further studies are needed to confirm the existence of differences between people of different income levels.