Dendritic cells are the most potent antigen-presenting cells (APC) and the most effective stimulators of primary T cell responses. Based on the strong influence of the APC on the immune response, we investigated cellular uptake of a biodegradable antigen delivery system, poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres, at two sites of injection: intraperitoneal and intradermal. We hypothesized that a fluorescent probe, tetramethylrhodamine labeled dextran, loaded in PLGA microspheres would be taken up by APCs and thereby provide a means for studying cellular uptake of PLGA microspheres in vivo. Phagocytic load and cell phenotype were determined using flow cytometry and confocal laser scanning microscopy. The results revealed cellular uptake of tetramethylrhodamine dextran loaded PLGA microspheres at both injection sites. After intraperitoneal immunization, the predominant cell phagocytosing PLGA microspheres in the peritoneal cavity was the macrophage whereas the intradermal immunization resulted in uptake of PLGA microspheres by dendritic cells. Hence, these results suggest that the profile for cellular uptake varies with the site of injection. More importantly, this study provides direct and conclusive evidence of uptake of PLGA microspheres by the most potent APC, the dendritic cell.

Bacterial infection leading to organ failure is the most common cause of death in critically ill patients. Early diagnosis and expeditious treatment is a cornerstone of therapy. Evaluating the systemic host response to infection as a complex system provides novel insights: however, bedside application with clinical value remains wanting. Providing an integrative measure of an altered host response, the patterns and character of heart rate fluctuations measured over intervals-in-time may be analysed with a panel of mathematical techniques that quantify overall fluctuation, spectral composition, scale-free variation, and degree of irregularity or complexity. Using these techniques, heart rate variability (HRV) has been documented to be both altered in the presence of systemic infection, and correlated with its severity. In this review and analysis, we evaluate the use of HRV monitoring to provide early diagnosis of infection, document the prognostic implications of altered HRV in infection, identify current limitations, highlight future research challenges, and propose improvement strategies. Given existing evidence and potential for further technological advances, we believe that longitudinal, individualized, and comprehensive HRV monitoring in critically ill patients at risk for or with existing infection offers a means to harness the clinical potential of this bedside application of complex systems science.

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