Margaret A. Myers

Influenza viruses cause a significant amount of morbidity and mortality. Understanding host immune control efficacy and how different factors influence lung injury and disease severity are critical. We established and validated dynamical connections between viral loads, infected cells, CD8 + T cells, lung injury, inflammation, and disease severity using an integrative mathematical model-experiment exchange. Our results showed that the dynamics of inflammation and virus-inflicted lung injury are distinct and nonlinearly related to disease severity, and that these two pathologic measurements can be independently predicted using the model-derived infected cell dynamics. Our findings further indicated that the relative CD8 + T cell dynamics paralleled the percent of the lung that had resolved with the rate of CD8 + T cell-mediated clearance rapidly accelerating by over 48,000 times in 2 days. This complimented our analyses showing a negative correlation between the efficacy of innate and adaptive immune-mediated infected cell clearance, and that infection duration was driven by CD8 + T cell magnitude rather than efficacy and could be significantly prolonged if the ratio of CD8 + T cells to infected cells was sufficiently low. These links between important pathogen kinetics and host pathology enhance our ability to forecast disease progression, potential complications, and therapeutic efficacy.

The effects of cortisol suppression by etomidate on the changes in circulating metabolites associated with pelvic surgery were investigated in healthy female patients. The use of etomidate resulted in the inhibition of cortisol secretion for 24 h compared with a control group of patients. However, the inhibition of steroidogenesis was not associated with a significant effect on blood glucose, blood lactate and plasma nonesterified fatty acid values, although the glycaemic response to surgery was consistently less in those patients who received etomidate. Heart rate and arterial pressure were significantly decreased during surgery in the etomidate group compared with the control group, but were similar in the postoperative period when the difference in plasma cortisol between the groups was greatest. The results suggest that cortisol has only a minor role in determining changes in circulating metabolites associated with surgery.

The stoichiometry of the sodium chloride cotransport system was examined in isolated perfused rectal glands of Squalus acanthias by kinetic analysis of the effect on chloride secretion of progressive substitutions of other ions for sodium and chloride in the perfusate. Secretion was stimulated by a constant infusion of dibutyryl cyclic AMP (5 X 10(-5) M) and theophylline (2.5 X 10(-4) M). Sodium was replaced by N-methyl-D-glucamine, whereas chloride was replaced by gluconate. The Km values for sodium, obtained using three different graphic methods, were close to or at the normal concentration of sodium in the plasma of the shark, suggesting that plasma sodium concentration regulates transport by the gland. The Km values for chloride were far below the normal concentration of chloride in the plasma, indicating that the chloride sites are normally saturated and therefore plasma chloride concentration cannot control transport by the gland. Hill plots revealed slopes of 1.06 for sodium and 1.6 for chloride, consistent with the hypothesis that 2 Cl- and 1 Na+ interact in the cotransport process. The cotransport linkage of 2 Cl- with 1 Na+ in the initial step of entry into the cell can be viewed as a device that doubles the energetic efficiency of salt transport, allowing 2 NaCl to be secreted for every 1 Na+ actively pumped.

The early time course of the acute phase protein response (APPR) and mediators involved in its control were investigated in the rat and mouse. After turpentine-induced inflammation in the rat C-reactive protein and fibrinogen increased in concentration peaking at 48 h and 18-24 h, respectively. A 9 h delay prior to elevation of these protein was observed. After injection of endotoxin into mice, a 4-6 h delay was observed prior to any increase in the concentration of the acute phase protein serum amyloid P-component. This delay was shortened to 2 h after injection of leucocytic endogenous mediators (LEM) produced from rabbit peritoneal exudate cells. It is concluded that the delay between the initiating stimulus and the increases in the acute phase proteins is due to some obligatory intermediate steps which lead to the production of the final mediators of the APPR, and that these mediators are present in LEM.