Synthesis and evaluation of sesquiterpene lactone inhibitors of phospholipase A(2) from Bothrops jararacussu

Several sesquiterpene lactone were synthesized and their inhibitive activities on phospholipase A(2) (PLA(2)) from Bothrops jararacussu venom were evaluated. Compounds Lac01 and Lac02 were efficient against PLA(2) edema-inducing, enzymatic and myotoxic activities and it reduces around 85% of myotoxicity and around 70% of edema-inducing activity. Lac05-Lac08 presented lower efficiency in inhibiting the biological activities studied and reduce the myotoxic and edema-inducing activities around only 15%. The enzymatic activity was significantly reduced. The values of inhibition constants (K(1)) for Lac01 and Lac02 were approximately 740 mu M, and for compounds Lac05-Lac08 the inhibition constants were approximately 7.622-9.240 mu M. The enzymatic kinetic studies show that the sesquiterpene lactones inhibit PLA(2) in a non-competitive manner. Some aspects of the structure-activity relationships (topologic, molecular and electronic parameters) were obtained using ab initio quantum calculations and analyzed by chemometric methods (HCA and PCA). The quantum chemistry calculations show that compounds with a higher capacity of inhibiting PLA(2) (Lac01-Lac04) present lower values of highest occupied molecular orbital (HOMO) energy and molecular volume (VOL) and bigger values of hydrophobicity (LogP). These results indicate some topologic aspects of the binding site of sesquiterpene lactone derivatives and PLA(2). (C) 2010 Elsevier Ltd. All rights reserved.

Corticosterone evaluation in Wistar rats infected with the Y strain of Trypanosoma cruzi during the chronic phase

Understanding the mechanisms responsible for mediating the effects of stress on Trypanosoma cruzi infection is crucial for determining the full impact of stress on Chagas` disease and for devising effective interventions. Dehydroepiandrosterone (DHEA), a steroid hormone synthesized from pregnenolone, is secreted by the adrenal cortex in response to stress. Although its physiologic role has not been fully defined, DHEA has been shown to modulate immune function. In the present study, we evaluated the levels of corticosterone and the ability of T. cruzi infection to modulate the expression of Th2 cytokines in Wistar rats with chronic Chagas` disease submitted to repetitive stress. The animals submitted to stress displayed enhanced levels of corticosterone as compared to control counterparts. Stress and infection triggered the most elevated concentrations of corticosterone. DHEA significantly reduced corticosterone levels for infected and stressed animals with DHEA. The infected animals displayed enhanced levels of IL-10 and IL-4 as compared to control ones. Stress combined with infection triggered the higher levels of IL-10 and IL-4. DHEA alone and combined with infection and stress significantly increased IL-10 and IL-4 levels. Then, this study might provide additional clues about factors that regulate some of the immunoregulatory aspects of T. cruzi infection and might offer new opportunities for therapeutic interventions. (C) 2010 Elsevier Inc. All rights reserved.

Evaluation of the genotoxicity of Crotalus durissus terrificus snake venom and its isolated toxins on human lymphocytes

In the present study, experiments were carried out to evaluate the mutagenic potential and genotoxic effects of Crotalus durissus terrificus snake venom and its isolated toxins on human lymphocytes, using the micronucleus and comet assays. Significant damage to DNA was observed for crotoxin and crotapotin (CA). Basic phospholipase A(2) (CB) and crotamine did not present any mutagenic potential when evaluated by the micronucleus test. C. d. terrificus crude venom was able to induce the formation of micronuclei, similarly to the mutagenic drug used as a positive control. In the comet assay, all the toxins tested (crotamine, crotoxin, CB and CA) and C. d. terrificus venom presented genotoxic activity. Studies on the cytogenetic toxicology of animal venoms and their isolated proteins are still very scarce in the literature, which emphasizes the importance of the present work for the identification and characterization of potential therapeutic agents, as well as for the better understanding of the mechanisms of action of toxins on the human body. (C) 2011 Elsevier B.V. All rights reserved.

In vitro evaluation of gastrointestinal survival of Lactobacillus amylovorus DSM 16698 alone and combined with galactooligosaccharides, milk and/or Bifidobacterium animalis subsp lactis Bb-12

Probiotic properties of Lactobacillus amylovorus DSM 16698 were previously demonstrated in piglets. Here, its potential as a human probiotic was studied in vitro, using the TIM-1 system, which is fully validated to simulate the human upper gastrointestinal tract. To evaluate the effect of the food matrix composition on the survival of L amylovorus DSM 16698 in TIM-1, the microorganism was inoculated alone or with prebiotic galactooligosaccharides (GOS), partially skimmed milk (PSM) and/or commercial probiotic Bifidobacterium animalis subsp. lactis Bb-12 (Bb-12). Samples were collected from TIM-1 for six hours, at one-hour intervals and L amylovorus populations were enumerated on MRS agar plates with confirmation of identity of selected isolates by randomly amplified polymorphic DNA (RAPD) fingerprinting. The cumulative survival for L amylovorus alone (control) was 30% at the end of the experiment (t = 6 h). Co-administration of L amylovorus with GOS. PSM and/or Bb-12 increased its survival in comparison with the control significantly from the 4th hour after ingestion onwards (P<0.05). Furthermore, by the use of High Performance Anion Exchange Chromatography, both L amylovorus and Bb-12 were observed to promptly degrade GOS compounds in samples collected from TIM-1, as assessed at t = 2 h. Hence, food matrix composition interfered with survival and growth of L. amylovorus during passage through TIM-1, providing leads towards optimization of probiotic properties in vivo. (C) 2011 Elsevier B.V. All rights reserved.

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

Evaluation of the genotoxic and antigenotoxic effects after acute and subacute treatments with acai pulp (Euterpe oleracea Mart.) on mice using the erythrocytes micronucleus test and the comet assay

Acai, the fruit of a palm native to the Amazonian basin, is widely distributed in northern South America, where it has considerable economic importance. Whereas individual polyphenolics compounds in Acai have been extensively evaluated, studies of the intact fruit and its biological properties are lacking. Therefore, the present study was undertaken to investigate the in vivo genotoxicity of Acai and its possible antigenotoxicity on doxorubicin (DXR)-induced DNA damage. The Acai pulp doses selected were 3.33, 10.0 and 16.67 g/kg b.w. administered by gavage alone or prior to DXR (16 mg/kg b.w.) administered by intraperitoneal injection. Swiss albino mice were distributed in eight groups for acute treatment with acai pulp (24 h) and eight groups for subacute treatment (daily for 14 consecutive days) before euthanasia. The negative control groups were treated in a similar way. The results of chemical analysis suggested the presence of carotenoids, anthocyanins, phenolic. and flavonoids in Acai pulp. The endpoints analyzed were micronucleus induction in bone marrow and peripheral blood cells polychromatic erythrocytes, and DNA damage in peripheral blood, liver and kidney cells assessed using the alkaline (pH > 13) comet assay. There were no statistically significant differences (p > 0.05) between the negative control and the groups treated with the three doses of Acai pulp alone in all endpoints analyzed, demonstrating the absence of genotoxic effects. The protective effects of Acai pulp were observed in both acute and subacute treatments, when administered prior to DXR. In general, subacute treatment provided greater efficiency in protecting against DXR-induced DNA damage in liver and kidney cells. These protective effects can be explained as the result of the phytochemicals present in Acai pulp. These results will be applied to the developmental of food with functional characteristics, as well as to explore the characteristics of Acai as a health promoter. (C) 2009 Elsevier B.V. All rights reserved.

Evaluation of dermatological effects of cosmetic formulations containing Saccharomyces cerevisiae extract and vitamins

Saccharomyces cerevisiae extract (SCE) is used in cosmetics since it can act in oxidative stress and improve skin conditions. This study investigated dermatological effects of cosmetic formulations containing SCE and/or vitamins A, C and E. The formulation studied was supplemented or not (F1: vehicle) with vitamins A, C and E esters (F2) or with SCE (F3) or with the combination of vitamins and SCE (F4). Formulations were patch tested on back skin of volunteers. For efficacy studies, formulations were applied on volunteers and transepidermal water loss (TEWL), skin moisture (SM), skin microrelief (SMR) and free radicals protection were analysed after 3 h, 15 and 30 days of application. Volunteers were also asked about efficacy perception. It was observed that F4 provoked a slight erythema in one volunteer. All formulations enhanced forearm SM. Only F3 and F4 presented long term effects on SMR and showed higher texture values; F3 had the highest brightness values. Our results suggest that vitamins and SCE showed effects in SM and SMR. Only formulations containing SC had long term effects in the improvement of SMR. Thus, these kinds of evaluations are very important in cosmetics development to evaluate the best risk and benefit correlation. (C) 2008 Elsevier Ltd. All rights reserved.

Evaluation of extractants for estimation of the phytoavailable trace metals in soils

Despite its environmental (and financial) importance, there is no agreement in the literature as to which extractant most accurately estimates the phytoavailability of trace metals in soils. A large dataset was taken from the literature, and the effectiveness of various extractants to predict the phytoavailability of Cd, Zn, Ni, Cu, and Pb examined across a range of soil types and contamination levels. The data suggest that generally, the total soil trace metal content, and trace metal concentrations determined by complexing agents (such as the widely used DTPA and EDTA extractants) or acid extractants (such as 0.1 M HCl and the Mehlich 1 extractant) are only poorly correlated to plant phytoavailability. Whilst there is no consensus, it would appear that neutral salt extractants (such as 0.01 M CaCl2 and 0.1 M NaNO3) provide the most useful indication of metal phytoavailability across a range of metals of interest, although further research is required.

Development and evaluation of neural network freeway incident detection models using field data

This paper discusses a multi-layer feedforward (MLF) neural network incident detection model that was developed and evaluated using field data. In contrast to published neural network incident detection models which relied on simulated or limited field data for model development and testing, the model described in this paper was trained and tested on a real-world data set of 100 incidents. The model uses speed, flow and occupancy data measured at dual stations, averaged across all lanes and only from time interval t. The off-line performance of the model is reported under both incident and non-incident conditions. The incident detection performance of the model is reported based on a validation-test data set of 40 incidents that were independent of the 60 incidents used for training. The false alarm rates of the model are evaluated based on non-incident data that were collected from a freeway section which was video-taped for a period of 33 days. A comparative evaluation between the neural network model and the incident detection model in operation on Melbourne's freeways is also presented. The results of the comparative performance evaluation clearly demonstrate the substantial improvement in incident detection performance obtained by the neural network model. The paper also presents additional results that demonstrate how improvements in model performance can be achieved using variable decision thresholds. Finally, the model's fault-tolerance under conditions of corrupt or missing data is investigated and the impact of loop detector failure/malfunction on the performance of the trained model is evaluated and discussed. The results presented in this paper provide a comprehensive evaluation of the developed model and confirm that neural network models can provide fast and reliable incident detection on freeways. (C) 1997 Elsevier Science Ltd. All rights reserved.

Reducing coronary heart disease in the Australian Coalfields: evaluation of a 10-year community intervention

Coronary heart disease is a leading cause of death in Australia with the Coalfields district of New South Wales having one of the country's highest rates. Identification of the Coalfields epidemic in the 1970's led to the formation of a community awareness program in the late 1980's (the healthy heart support group) followed by a more intense community action program in 1990, the Coalfields Healthy Heartbeat (CHHB). CHHB is a coalition of community members, local government officers, health workers and University researchers. We evaluate the CHHB program, examining both the nature and sustainability of heart health activities undertaken, as well as trends in risk factor levels and rates of coronary events in the Coalfields in comparison with nearby local government areas. Process data reveal difficulties mobilising the community as a whole; activities had to be selected for interested subgroups such as families of heart disease patients, school children, retired people and women concerned with family nutrition and body maintenance. Outcome data show a significantly larger reduction in case fatality for Coalfields men (although nonfatal heart attacks did not decline) while changes in risk factors levels were comparable with surrounding areas. We explain positive responses to the CHHB by schools, heart attack survivors and women interested in body maintenance in terms of the meaning these subgroups find in health promotion discourses based on their embodied experiences. When faced with a threat to one's identity, health discourse suddenly becomes meaningful along with the regimens for health improvement. General public disinterest in heart health promotion is examined in the context of historical patterns of outsiders criticising the lifestyle of miners, an orientation toward communal lather than individual responsibility for health (i.e, community 'owned' emergency services and hospitals) and anger about risks from environmental hazards imposed by industrialists. (C) 1999 Elsevier Science Ltd. All rights reserved.

An evaluation of the time dependence of the anisotropy of the water diffusion tensor in acute human ischemia

We have performed MRI examinations to determine the water diffusion tensor in the brain of six patients who were admitted to the hospital within 12 h after the onset of cerebral ischemic symptoms. The examinations have been carried out immediately after admission, and thereafter at varying intervals up to 90 days post admission. Maps of the trace of the diffusion tensor, the fractional anisotropy and the lattice index, as well as maps of cerebral blood perfusion parameters, were generated to quantitatively assess the character of the water diffusion tensor in the infarcted area. In patients with significant perfusion deficits and substantial lesion volume changes, four of six cases, our measurements show a monotonic and significant decrease in the diffusion anisotropy within the ischemic lesion as a function of time. We propose that retrospective analysis of this quantity, in combination with brain tissue segmentation and cerebral perfusion maps, may be used in future studies to assess the severity of the ischemic event. (C) 1999 Elsevier Science Inc.

Evaluation of a new bioelectrical impedance instrument for the prediction of body cell mass independently of height or weight

The objective of the present study was to evaluate the performance of a new bioelectrical impedance instrument, the Soft Tissue Analyzer (STA), which predicts a subject's body composition. A cross-sectional population study in which the impedance of 205 healthy adult subjects was measured using the STA. Extracellular water (ECW) volume (as a percentage of total body water, TBW) and fat-free mass (FFM) were predicted by both the STA and a compartmental model, and compared according to correlation and limits of agreement analysis, with the equivalent data obtained by independent reference methods of measurement (TBW measured by D2O dilution, and FFM measured by dual-energy X-ray absorptiometry). There was a small (2.0 kg) but significant (P < 0.02) difference in mean FFM predicted by the STA, compared with the reference technique in the males, but not in the females (-0.4 kg) or in the combined group (0.8 kg). Both methods were highly correlated. Similarly, small but significant differences for predicted mean ECW volume were observed. The limits of agreement for FFM and ECW were -7.5-9.9 and -4.1-3.0 kg, respectively. Both FFM and ECW (as a percentage of TBW) are well predicted by the STA on a population basis, but the magnitude of the limits of agreement with reference methods may preclude its usefulness for predicting body composition in an individual. In addition, the theoretical basis of an impedance method that does not include a measure of conductor length requires further validation. (C) Elsevier Science Inc. 2000.

The role of economic evaluation in mental health care

Objective: A consequence of the integration of psychiatry into acute and public health medicine is that psychiatrists are being asked to evaluate their services. There is pressure on mental health-care systems because it is recognized that funds should be directed where they can provide the best health outcomes, and also because there are resource constraints which limit our capacity to meet all demands for health care. This pressure can be responded to by evaluation which demonstrates the effectiveness and efficiency of psychiatric treatment. This paper seeks to remind psychiatrists of the fundamental principles of economic evaluation in the hope that these will enable psychiatrists to understand the methods used in evaluation and to work comfortably with evaluators. Method: The paper reviews the basic principles behind economic evaluation, illustrating these with reference to case studies. It describes: (i) the cost of the burden of illness and treatment, and how these costs are measured; (ii) the measurement of treatment outcomes, both as changes in health status and as resources saved; and (iii) the various types of economic evaluation, including cost-minimization, cost-effectiveness, cost-utility and cost-benefit analysis. Results: The advice in the paper provides psychiatrists with the necessary background to work closely with evaluators. A checklist of the critical questions to be addressed is provided as a guide for those undertaking economic evaluations. Conclusions: If psychiatrists are willing to learn the basic principles of economic evaluation and to apply these, they can respond to the challenges of evaluation.

Modelling solute transport in structured soils: Performance evaluation of the ADR and TRM models

The movement of chemicals through the soil to the groundwater or discharged to surface waters represents a degradation of these resources. In many cases, serious human and stock health implications are associated with this form of pollution. The chemicals of interest include nutrients, pesticides, salts, and industrial wastes. Recent studies have shown that current models and methods do not adequately describe the leaching of nutrients through soil, often underestimating the risk of groundwater contamination by surface-applied chemicals, and overestimating the concentration of resident solutes. This inaccuracy results primarily from ignoring soil structure and nonequilibrium between soil constituents, water, and solutes. A multiple sample percolation system (MSPS), consisting of 25 individual collection wells, was constructed to study the effects of localized soil heterogeneities on the transport of nutrients (NO3-, Cl-, PO43-) in the vadose zone of an agricultural soil predominantly dominated by clay. Very significant variations in drainage patterns across a small spatial scale were observed tone-way ANOVA, p < 0.001) indicating considerable heterogeneity in water flow patterns and nutrient leaching. Using data collected from the multiple sample percolation experiments, this paper compares the performance of two mathematical models for predicting solute transport, the advective-dispersion model with a reaction term (ADR), and a two-region preferential flow model (TRM) suitable for modelling nonequilibrium transport. These results have implications for modelling solute transport and predicting nutrient loading on a larger scale. (C) 2001 Elsevier Science Ltd. All rights reserved.

An economic evaluation of plasma production via erythroplasmapheresis and whole blood collection

This paper presents cost-effectiveness analyses (CEAs) of plasma collection via two alternative methods: whole blood collection (WBC) and erythroplasmapheresis collection (EPC). The objective of the study is to provide an answer to the question 'What is the least-cost method of plasma production'. This question is answered, both from the viewpoint of the blood collection agency (using financial CEA) and from that of 'society' as a whole (using economic CEA). We employ detailed financial data and economic survey data for collections made by a blood collection agency and to WBC and EPC donors in Brisbane, Australia. The results indicate that, despite the superior yield provided by EPC, WBC is actually more cost-effective. This result is robust to thorough sensitivity analysis and arises regardless of whether an economic or financial perspective is taken. We conclude that, ceteris paribus, the cost of recruiting new plasma donors would need to be quite substantial for marginal investments in EPC to be considered cost-effective. Crown Copyright (C) 2002 Published by Elsevier Science Ltd. All rights reserved.