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This article examines the effects of maximal exercise on calcium homeostasis of lymphocytes and related changes in cellular signal transduction. Findings indicate that exhaustive exercise results in an immediate increase in intracellular calcium and lymphocyte subsets, such as natural killer and T cells, and significantly influences intracellular signaling of lymphocytes.

Vaccination with BCG, an attenuated strain of bovine tubercle bacilli, has been used for most of this century to protect against tuberculosis.[1] Recently the cell mediated immune response that follows [...]

ABSTRACTNutritional status may have a profound impact on the pharmacokinetics of drugs, yet only few data are available for tuberculosis (TB) drugs. As malnutrition occurs frequently among TB patients, we assessed the effect of malnutrition on the steady-state pharmacokinetics of total and protein-unbound rifampin during the intensive phase of TB treatment. In a descriptive pharmacokinetic study in Bandung, Indonesia, patients received a fixed standard rifampin dose of 450 mg once daily during the intensive phase of TB treatment. A full pharmacokinetic curve for rifampin was recorded, and total and unbound concentrations of rifampin were analyzed in all samples. Rifampin pharmacokinetic parameters were compared between severely malnourished (BMI of <16.0 kg/m2), malnourished (BMI of <18.5 kg/m2), and well-nourished (BMI of ≥18.5 kg/m2) individuals. No difference in total and protein-unbound pharmacokinetic parameters between severely malnourished (n= 7), malnourished (n= 11), and well-nourished (n= 25) patients could be demonstrated. In addition, no significant correlation between BMI and exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24] and maximum concentration of drug in serum [Cmax]) was found. Females had significantly higher total AUC0–24(geometric mean, 59.2 versus 48.2 h · mg/liter; P= 0.02) and higher unbound AUC0–24(geometric mean, 6.2 versus 4.8 h · mg/liter; P= 0.02) than males. Overall, a marked 2-fold interindividual variation in the free fraction was observed (7.6 to 15.0%; n= 36). Nutritional status and BMI do not appear to have a major effect on total and protein-unbound pharmacokinetic parameters of rifampin in Indonesian subjects. The large interindividual variability in the free fraction of rifampin suggests that protein-unbound rather than total rifampin concentrations should preferably be used to study exposure-response relationships.

Proteinase‐activated receptor‐2 (PAR2) belongs to a novel subfamily of G‐protein‐coupled receptors with seven‐transmembrane domains. PAR2can be activated by serine proteases such as trypsin, mast cell tryptase, and allergic or bacterial proteases. This receptor is expressed by various cells and seems to be crucially involved during inflammation and the immune response. As previously reported, human neutrophils express functional PAR2. However, the precise physiological role of PAR2on human neutrophils and its implication in human diseases remain unclear. We demonstrate that PAR2agonist‐stimulated human neutrophils show significantly enhanced migration in 3‐D collagen lattices. PAR2agonist stimulation also induced down‐regulation of L‐selectin display and up‐regulation of membrane‐activated complex‐1 very late antigen‐4 integrin expression on the neutrophil cell surface. Moreover, PAR2stimulation results in an increased secretion of the cytokines interleukin (IL)‐1β, IL‐8, and IL‐6 by human neutrophils. These data indicate that PAR2plays an important role in human neutrophil activation and may affect key neutrophil functions by regulating cell motility in the extracellular matrix, selectin shedding, and up‐regulation of integrin expression and by stimulating the secretion of inflammatory mediators. Thus, PAR2may represent a potential therapeutic target for the treatment of diseases involving activated neutrophils.

Apoptosis or programmed cell death is a process of fundamental importance for regulation of the immune response. Several reasons suggest that apoptosis is involved in exercise-induced alterations of the immune system such as postexercise lymphocytopenia. Healthy volunteers performed two treadmill exercise tests; the first was performed at 80% maximal oxygen uptake until exhaustion (exhaustive exercise) and the second 2 wk later at 60% maximal oxygen uptake with the identical running time (moderate exercise). Blood samples were taken before, immediately after, and 1 h after the test. Lymphocytes were analyzed for apoptotic and necrotic cells by using FITC-labeled annexin V-antibodies and nuclear propidium iodide uptake, respectively. In addition, apoptotic/necrotic cells were measured after a 24-h incubation of lymphocytes in the presence of camptothecin or phytohemagglutinin. Finally, plasma membrane expression of CD95-receptor and CD95-receptor ligand was investigated. Immediately after the exhaustive exercise, the percentage of apoptotic cells increased significantly, whereas it remained unchanged after the moderate exercise. Similar results were obtained after 24-h incubation of lymphocytes in medium alone or in the presence of camptothecin, but not with phytohemagglutinin. We found an upregulation of CD95-receptor expression after both exercise tests. However, only after exhaustive exercise a characteristic shift in CD95 expression profile toward cells with a high receptor density was observed. Expression of the CD95-receptor ligand remained unchanged after both exhaustive and moderate exercise. These results suggest that apoptosis may contribute to the regulation of the immune response after exhaustive exercise. Whether this mechanism can be regarded either as beneficial, i.e., deletion of autoreactive cells, or harmful, i.e., suppression of the immune response, awaits further investigations.