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Mechanisms by which the intestinal epithelium resists invasion by food-borne pathogens such as Listeria monocytogenes are an evolving area of research. Intestinal P glycoprotein is well known to limit the absorption of xenobiotics and is believed to act as a cytotoxic defense mechanism. The aim of this study was to determine if intestinal P glycoprotein is involved in host defense against L. monocytogenes. Caco-2 cells and a Pglycoprotein-overexpressing subclone (Caco-2/MDR) were employed in addition to mdr1a ؊/؊ mice and wildtype controls. In vitro invasion assays and in vivo experiments were employed to measure bacterial invasion and dissemination. In addition, L. monocytogenes proteins were labeled with [35 S]methionine, and the transepithelial transport across Caco-2 monolayers was characterized in both directions. Overexpression of P glycoprotein in Caco-2/MDR cells led to increased resistance to L. monocytogenes invasion, whereas P-glycoprotein inhibition led to increased invasion. Flux of [35 S]methionine-labeled L. monocytogenes proteins was significantly greater in the basolateral-to-apical direction than in the apical-to-basolateral direction, indicating dependence on an apically located efflux transporter. Moreover, inhibiting P glycoprotein reduced the basolateral-to-apical flux of the proteins. Early dissemination of L. monocytogenes from the gastrointestinal tract was significantly greater in the mdr1a ؊/؊ mice than in wild-type controls. Expression and function of intestinal P glycoprotein is an important determinant in resistance to early invasion of L. monocytogenes.P glycoprotein is the 170-kDa product of the human MDR1 gene and is arguably one of the most extensively studied members of the ATP-binding cassette superfamily of transport proteins (28). P glycoprotein is best known for its ability to transport drug substrates out of cells in a variety of tissues, including the intestine (1,12,27). Both the expression and the function of P glycoprotein have been linked to considerable variability in oral drug absorption; however, the precise physiological role of intestinal P glycoprotein is unknown. Because P glycoprotein is well conserved throughout evolution and has a broad substrate affinity, it is widely believed to act as a cytotoxic protection mechanism. Given its apical distribution on the enterocyte, P glycoprotein is exquisitely positioned to limit the absorption of substances that the cell perceives as harmful. Thus, it is conceivable that P glycoprotein restricts the absorption of other, nondrug substances in the intestine. Proteins facilitating invasion of pathogenic bacteria would be ideal candidates given the purported mechanism of action of P glycoprotein.Listeria monocytogenes is a food-borne pathogen responsible for considerable morbidity and mortality (11,24). Although multiple sites of invasion have been proposed, the vanguard of the body's interaction with L. monocytogenes is the intestinal epithelial barrier. Intestinal epithelial cells come in contact with not only the bacter...

Elevated intracranial pressure occurs frequently in patients with severe head injury. A number of studies in recent years suggest that indomethacin may be useful in the management of elevated intracranial pressure. Indomethacin acts primarily by reducing cerebral blood flow and decreasing cerebral edema following head injury. This review summarizes the basic and clinical studies of the effects of indomethacin on cerebral blood flow, brain edema, and intracranial pressure. The pharmacology of indomethacin, and issues for future investigation in the use of indomethacin in severe head injury, are discussed.

Serotype 4b strains of Listeria monocytogenes have been responsible for most large outbreaks of listeriosis. In L. monocytogenes serotype 4b, gtcA and gltA have been implicated in serotype-specific glycosylation of the teichoic acid of the cell wall with galactose and glucose. In this study, we investigated the impact of mutations in gltA (resulting in absence of glucose on teichoic acid) and gtcA (resulting in absence of galactose, and markedly reduced glucose on teichoic acid) on virulence following intragastric infection of anesthetized A/J mice. The gltA mutant was not impaired in virulence in this model. In contrast, testing of gtcA mutants constructed in two different strains showed that the mutants were recovered in lower numbers than their respective parent strains from the spleen, liver, ceca, and gall bladders of intragastrically inoculated mice. Genetic complementation of the gtcA mutation partially restored gastrointestinal virulence. When mice were inoculated intravenously, the gtcA mutants were also recovered in lower numbers from the liver (for both mutant strains) and the spleen (for one mutant strain) than their respective parental strains. The mutants were also evaluated for invasion and intracellular multiplication in the Caco-2 human intestinal epithelial cell line. Inactivation of gltA did not affect invasion or intracellular growth of the bacteria. In contrast, gtcA mutants showed decreased invasion, but normal multiplication in Caco-2 cells. Overall, these data demonstrate a role for gtcA in the pathogenesis of gastrointestinal listeriosis in mice, and suggest that diminished ability of gtcA mutants to invade intestinal epithelial cells may be partly responsible for decreased gastrointestinal virulence.

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Heart failure is a growing cardiovascular disease with significant epidemiological, clinical, and societal implications and represents a high unmet need. Strong efforts are currently underway by academic and industrial researchers to develop novel treatments for heart failure. Biomarkers play an important role in patient selection and monitoring in drug trials and in clinical management. The present review gives an overview of the role of available molecular, imaging, and device-derived digital biomarkers in heart failure drug development and highlights capabilities and limitations of biomarker use in this context.

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