Kinetics of T cell-activation molecules in response to Mycobacterium tuberculosis antigens

The phenotypic features acquired subsequent to antigen-specific stimulation in vitro were evaluated by means of the kinetic expressions of CD69 and CD25 activation molecules on T lymphocytes and assayed by flow cytometry in response to PPD, Ag85B, and ferritin in PPD-positive healthy control individuals. In response to PHA, CD69 staining on both CD4+ and CD8+ T cells became initially marked after 4 h, peaked at 24 h, and quickly decreased after 120 h. For CD25, a latter expression was detected around 8 h, having increased after 96 h. As expected, the response rate to the mycobacterial antigens was much lower than that to the mitogen. Positive staining was high after 96 h for CD25 and after 24 h for CD69. CD69 expression was significantly enhanced (p < 0.05) on CD8+ as compared to CD4+ T cells. High levels were also found between 96-120 h. Regarding Ag85B, CD25+ cells were mostly CD4+ instead of CD8+ T cells. Moreover, in response to ferritin, a lower CD25 expression was noted. The present data will allow further characterization of the immune response to new mycobacterial-specific antigens and their evaluation for possible inclusion in developing new diagnostic techniques for tuberculosis as well in a new vaccine to prevent the disease.

On the analysis of travelling waves to a nonlinear flux limited reaction-diffusion equation

In this paper we study the existence and qualitative properties of travelling waves associated to a nonlinear flux limited partial differential equation coupled to a Fisher-Kolmogorov-Petrovskii-Piskunov type reaction term. We prove the existence and uniqueness of finite speed moving fronts of C2 classical regularity, but also the existence of discontinuous entropy travelling wave solutions.

Step this way for better health

This leaflet explains how to use a step counter to motivate yourself to do more walking. It includes a step log to encourage walkers to monitor and record their progress.

Experimental kinetics of infection induced by Yersinia pseudotuberculosis isolated from stock animals

The course of in vivo infection of five isolates of Yersinia pseudotuberculosis was followed for three weeks in Swiss mice. The strains were isolated from diarrheic and normal feces and mesenteric lymph nodes of healthy and sick stock animals. Four strains of serogroup O:3 and one of serogroup O:1a, with and without the virulence plasmid, were inoculated intragastrically and intravenously in the mice. Groups of five animals were sacrificed at 6 h and 3, 6, 10, 15, and 21 days after inoculation, and organs and tissues were checked for possible macroscopic alterations. Development of infection was monitored at these times by performing viable bacterial counts in homogenates of selected tissues. The animals were cheked daily for clinical alterations. The results of the study showed that strains with the virulence plasmid infected organs and tissues at various times and at varying intensity by both routes of infection, the strain of type O:1a being the most invasive. Moreover, clinical and pathological alterations occurred only in animals inoculated with bacteria carrying the virulence plasmid, regardless of the route of infection.

A simple way to decompress the left ventricle during venoarterial bypass

OBJECTIVE: The aim of this investigation was to improve the hemodynamics during venoarterial bypass by remote decompression of the left ventricle (LV). METHODS: Venoarterial bypass was established in 5 bovine experiments (69+/-10 kg) by the transjugular insertion of a self-expanding cannula (smartcanula) with return through a carotid artery. Cardiogenic shock was simulated with ventricular fibrillation induced by an external stimulator. Left ventricular decompression was achieved by switching to transfemoral drainage of the pulmonary artery (PA) with a long self-expanding cannula. RESULTS: Initial pump flow was 4.7+/-0.9 l/min and the aortic pressure accounted for 75+/-21 mmHg. After induction of ventricular fibrillation, the pump flow dropped after 11+/-8 min to 2.5+/-0.1 l/min. Transfemoral decompression increased the pump flow to 5.6+/-0.7 l/min, while the RV pressure decreased from 27+/-9 to 3+/-5 mmHg, the PA pressure decreased from 29+/-7 to 5+/-4 mmHg, the LV pressure decreased from 29+/-6 to 7+/-2 mmHg, and the aortic pressure increased from 31+/-3 to 47+/-11 mmHg. CONCLUSIONS: Remote drainage of the pulmonary artery during venoarterial bypass allows for effective decompression of the left ventricle and provides superior hemodynamics.

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

The modern approach to the development of new chemical entities against complex diseases, especially the neglected endemic diseases such as tuberculosis and malaria, is based on the use of defined molecular targets. Among the advantages, this approach allows (i) the search and identification of lead compounds with defined molecular mechanisms against a defined target (e.g. enzymes from defined pathways), (ii) the analysis of a great number of compounds with a favorable cost/benefit ratio, (iii) the development even in the initial stages of compounds with selective toxicity (the fundamental principle of chemotherapy), (iv) the evaluation of plant extracts as well as of pure substances. The current use of such technology, unfortunately, is concentrated in developed countries, especially in the big pharma. This fact contributes in a significant way to hamper the development of innovative new compounds to treat neglected diseases. The large biodiversity within the territory of Brazil puts the country in a strategic position to develop the rational and sustained exploration of new metabolites of therapeutic value. The extension of the country covers a wide range of climates, soil types, and altitudes, providing a unique set of selective pressures for the adaptation of plant life in these scenarios. Chemical diversity is also driven by these forces, in an attempt to best fit the plant communities to the particular abiotic stresses, fauna, and microbes that co-exist with them. Certain areas of vegetation (Amazonian Forest, Atlantic Forest, Araucaria Forest, Cerrado-Brazilian Savanna, and Caatinga) are rich in species and types of environments to be used to search for natural compounds active against tuberculosis, malaria, and chronic-degenerative diseases. The present review describes some strategies to search for natural compounds, whose choice can be based on ethnobotanical and chemotaxonomical studies, and screen for their ability to bind to immobilized drug targets and to inhibit their activities. Molecular cloning, gene knockout, protein expression and purification, N-terminal sequencing, and mass spectrometry are the methods of choice to provide homogeneous drug targets for immobilization by optimized chemical reactions. Plant extract preparations, fractionation of promising plant extracts, propagation protocols and definition of in planta studies to maximize product yield of plant species producing active compounds have to be performed to provide a continuing supply of bioactive materials. Chemical characterization of natural compounds, determination of mode of action by kinetics and other spectroscopic methods (MS, X-ray, NMR), as well as in vitro and in vivo biological assays, chemical derivatization, and structure-activity relationships have to be carried out to provide a thorough knowledge on which to base the search for natural compounds or their derivatives with biological activity.

Version brève du DISCERN, une voie d'amélioration de la recherche d'information médicale sur le net [Brief-DISCERN, a possible way to improve patient's search on the health-related web]

Internet is increasingly used as a source of information on health issues and is probably a major source of patients' empowerment. This process is however limited by the frequently poor quality of web-based health information designed for consumers. A better diffusion of information about criteria defining the quality of the content of websites, and about useful methods designed for searching such needed information, could be particularly useful to patients and their relatives. A brief, six-items DISCERN version, characterized by a high specificity for detecting websites with good or very good content quality was recently developed. This tool could facilitate the identification of high-quality information on the web by patients and may improve the empowerment process initiated by the development of the health-related web.

Gender differences in whole-body fat oxidation kinetics during exercise.

Discrepancies appear in studies comparing fat oxidation between men and women. Therefore, this study aimed to quantitatively describe and compare whole-body fat oxidation kinetics between genders during exercise, using a sinusoidal (SIN) model. Twelve men and 11 women matched for age, body mass index, and aerobic fitness (maximal oxygen uptake and maximal power output per kilogram of fat-free mass (FFM)) performed submaximal incremental tests (Incr) with 5-min stages and a 7.5% maximal power output increment on a cycle ergometer. Fat oxidation rates were determined using indirect calorimetry, and plotted as a function of exercise intensity. The SIN model, which includes 3 independent variables (dilatation, symmetry, translation) that account for the main quantitative characteristics of kinetics, was used to mathematically describe fat oxidation kinetics and to determine the intensity (Fatmax) eliciting the maximal fat oxidation (MFO). During Incr, women exhibited greater fat oxidation rates from 35% to 85% maximal oxygen uptake, MFO (6.6 ± 0.9 vs. 4.5 ± 0.3 mg·kg FFM-1·min-1), and Fatmax (58.1% ± 1.9% vs. 50.0% ± 2.7% maximal oxygen uptake) than men (p < 0.05). While men and women showed similar global shapes of fat oxidation kinetics in terms of dilatation and symmetry (p > 0.05), the fat oxidation curve tended to be shifted toward higher exercise intensities in women (rightward translation, p = 0.08). These results support the idea that women have a greater reliance on fat oxidation than men during submaximal exercise, but also indicate that this greater fat oxidation is shifted toward higher exercise intensities in women than in men.

This white line will affect the way you see this one

This poster raises awareness about the danger of taking drugs and driving. The message on the poster is 'Drugs affect your driving - Never take drugs and drive.' It also provides contact details for the National Drugs Helpline. Tel: 0800 776600.

Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients.

BACKGROUND: Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability. METHODS: Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM®). RESULTS: A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs' pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients. CONCLUSION: The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.

Effect of acute and chronic exercise on fat oxidation and hormonal and plasma metabolite kinetics in obese and severely obese men

Acute exercise increases energy expenditure (EE) during exercise and post-exercise recovery [excess post-exercise oxygen consumption (EPOC)] and therefore may be recommended as part of the multidisciplinary management of obesity. Moreover, chronic exercise (training) effectively promotes an increase in insulin sensitivity, which seems to be associated with increased fat oxidation rates (FORs). The main purpose of this thesis is to investigate 1) FORs and extra-muscular factors (hormones and plasma metabolites) that regulate fat metabolism during acute and chronic exercise; and 2) EPOC during acute post-exercise recovery in obese and severely obese men (class II and III). In the first study, we showed that obese and severely obese men present a lower exercise intensity (Fatmax) eliciting maximal fat oxidation and a lower reliance on fat oxidation at high, but not at low and moderate, exercise intensities compared to lean men. This was most likely related to an impaired muscular capacity to oxidize non-esterified fatty acids (NEFA) rather than decreased plasma NEFA availability or a change in the hormonal milieu during exercise. In the second study, we developed an accurate maximal incremental test to correctly and simultaneously evaluate aerobic fitness and fat oxidation kinetics during exercise in this population. This test may be used for the prescription of an appropriate exercise training intensity. In the third study, we demonstrated that only 2 wk of exercise training [continuous training at Fatmax and adapted high-intensity interval training (HIIT)], matched with respect to mechanical work, may be effective to improve aerobic fitness, FORs during exercise and insulin sensitivity, which suggest that FORs might be rapidly improved and that adapted HIIT is feasible in this population. The increased FORs concomitant with the lack of changes in lipolysis during exercise suggest an improvement in the mismatching between NEFA availability and oxidation, highlighting the importance of muscular (oxidative capacity) rather than extra-muscular (hormones and plasma metabolites) factors in the regulation of fat metabolism after a training program. In the fourth study, we observed a positive correlation between EE during exercise and EPOC, suggesting that a chronic increase in the volume or intensity of exercise may increase EE during exercise and during recovery. This may have an impact in weight management in obesity. In conclusion, these findings might have practical implications for exercise training prescriptions in order to improve the therapeutic approaches in obesity and severe obesity. -- L'exercice aigu augmente la dépense énergétique (DE) pendant l'exercice et la récupération post-exercice [excès de consommation d'oxygène post-exercise (EPOC)] et peut être utilisé dans la gestion multidisciplinaire de l'obésité. Quant à l'exercice chronique (entraînement), il est efficace pour augmenter la sensibilité à l'insuline, ce qui semble être associé à une amélioration du débit d'oxydation lipidique (DOL). Le but de cette thèse est d'étudier 1) le DOL et les facteurs extra-musculaires (hormones et métabolites plasmatiques) qui régulent le métabolisme lipidique pendant l'exercice aigu et chronique et 2) l'EPOC lors de la récupération aiguë post-exercice chez des hommes obèses et sévèrement obèses (classe II et III). Dans la première étude nous avons montré que les hommes obèses et sévèrement obèses présentent une plus basse intensité d'exercice (Fatmax) correspondant au débit d'oxydation lipidique maximale et un plus bas DOL à hautes, mais pas à faibles et modérées, intensités d'exercice comparé aux sujets normo-poids, ce qui est probablement lié à une incapacité musculaire à oxyder les acides gras non-estérifiés (AGNE) plutôt qu'à une diminution de leur disponibilité ou à un changement du milieu hormonal pendant l'exercice. Dans la deuxième étude nous avons développé un test maximal incrémental pour évaluer simultanément l'aptitude physique aérobie et la cinétique d'oxydation des lipides pendant l'exercice chez cette population. Dans la troisième étude nous avons montré que seulement deux semaines d'entraînement (continu à Fatmax et intermittent à haute intensité), appariés par la charge de travail, sont efficaces pour améliorer l'aptitude physique aérobie, le DOL pendant l'exercice et la sensibilité à l'insuline, ce qui suggère que le DOL peut être rapidement amélioré chez cette population. Ceci, en absence de changements de la lipolyse pendant l'exercice, suggère une amélioration de la balance entre la disponibilité et l'oxydation des AGNE, ce qui souligne l'importance des facteurs musculaires (capacité oxydative) plutôt que extra-musculaires (hormones et métabolites plasmatiques) dans la régulation du métabolisme lipidique après un entraînement. Dans la quatrième étude nous avons observé une corrélation positive entre la DE pendant l'exercice et l'EPOC, ce qui suggère qu'une augmentation chronique du volume ou de l'intensité de l'exercice pourrait augmenter la DE lors de l'exercice et lors de la récupération post-exercice. Ceci pourrait avoir un impact sur la gestion du poids chez cette population. En conclusion, ces résultats pourraient avoir des implications pratiques lors de la prescription des entraînements dans le but d'améliorer les approches thérapeutiques de l'obésité et de l'obésité sévère.

Effect of inspiratory threshold loading on ventilatory kinetics during constant-load exercise.

Humoral factors play an important role in the control of exercise hyperpnea. The role of neuromechanical ventilatory factors, however, is still being investigated. We tested the hypothesis that the afferents of the thoracopulmonary system, and consequently of the neuromechanical ventilatory loop, have an influence on the kinetics of oxygen consumption (VO2), carbon dioxide output (VCO2), and ventilation (VE) during moderate intensity exercise. We did this by comparing the ventilatory time constants (tau) of exercise with and without an inspiratory load. Fourteen healthy, trained men (age 22.6 +/- 3.2 yr) performed a continuous incremental cycle exercise test to determine maximal oxygen uptake (VO2max = 55.2 +/- 5.8 ml x min(-1) x kg(-1)). On another day, after unloaded warm-up they performed randomized constant-load tests at 40% of their VO2max for 8 min, one with and the other without an inspiratory threshold load of 15 cmH2O. Ventilatory variables were obtained breath by breath. Phase 2 ventilatory kinetics (VO2, VCO2, and VE) could be described in all cases by a monoexponential function. The bootstrap method revealed small coefficients of variation for the model parameters, indicating an accurate determination for all parameters. Paired Student's t-tests showed that the addition of the inspiratory resistance significantly increased the tau during phase 2 of VO2 (43.1 +/- 8.6 vs. 60.9 +/- 14.1 s; P < 0.001), VCO2 (60.3 +/- 17.6 vs. 84.5 +/- 18.1 s; P < 0.001) and VE (59.4 +/- 16.1 vs. 85.9 +/- 17.1 s; P < 0.001). The average rise in tau was 41.3% for VO2, 40.1% for VCO2, and 44.6% for VE. The tau changes indicated that neuromechanical ventilatory factors play a role in the ventilatory response to moderate exercise.

(.)VO(2) and EMG activity kinetics during moderate and severe constant work rate exercise in trained cyclists.

The purpose of this study was to compare O(2) uptake ((.)VO(2)) and muscle electromyography activity kinetics during moderate and severe exercise to test the hypothesis of progressive recruitment of fast-twitch fibers in the explanation of the VO(2) slow component. After an incremental test to exhaustion, 7 trained cyclists (mean +/- SD, 61.4 +/- 4.2 ml x min(-1) x kg(- 1)) performed several square-wave transitions for 6 min at moderate and severe intensities on a bicycle ergometer. The (.)VO(2) response and the electrical activity (i.e., median power frequency, MDF) of the quadriceps vastus lateralis and vastus medialis of both lower limbs were measured continuously during exercise. After 2 to 3 min of exercise onset, MDF values increased similarly during moderate and severe exercise for almost all muscles whereas a (.)VO(2) slow component occurred during severe exercise. There was no relationship between the increase of MDF values and the magnitude of the (.)VO(2) slow component during the severe exercise. These results suggest that the origin of the slow component may not be due to the progressive recruitment of fast-twitch fibers.

Addition of inspiratory resistance increases the amplitude of the slow component of O2 uptake kinetics.

The contribution of respiratory muscle work to the development of the O(2) consumption (Vo(2)) slow component is a point of controversy because it has been shown that the increased ventilation in hypoxia is not associated with a concomitant increase in Vo(2) slow component. The first purpose of this study was thus to test the hypothesis of a direct relationship between respiratory muscle work and Vo(2) slow component by manipulating inspiratory resistance. Because the conditions for a Vo(2) slow component specific to respiratory muscle can be reached during intense exercise, the second purpose was to determine whether respiratory muscles behave like limb muscles during heavy exercise. Ten trained subjects performed two 8-min constant-load heavy cycling exercises with and without a threshold valve in random order. Vo(2) was measured breath by breath by using a fast gas exchange analyzer, and the Vo(2) response was modeled after removal of the cardiodynamic phase by using two monoexponential functions. As anticipated, when total work was slightly increased with loaded inspiratory resistance, slight increases in base Vo(2), the primary phase amplitude, and peak Vo(2) were noted (14.2%, P < 0.01; 3.5%, P > 0.05; and 8.3%, P < 0.01, respectively). The bootstrap method revealed small coefficients of variation for the model parameter, including the slow-component amplitude and delay (15 and 19%, respectively), indicating an accurate determination for this critical parameter. The amplitude of the Vo(2) slow component displayed a 27% increase from 8.1 +/- 3.6 to 10.3 +/- 3.4 ml. min(-1). kg(-1) (P < 0.01) with the addition of inspiratory resistance. Taken together, this increase and the lack of any differences in minute volume and ventilatory parameters between the two experimental conditions suggest the occurrence of a Vo(2) slow component specific to the respiratory muscles in loaded condition.