Cardiac troponin T and cardiac dysfunction in extremely low-birth-weight infants.

Extremely low-birth-weight (ELBW) infants frequently manifest signs of cardiac dysfunction requiring inotropic support. It is not clear if this is due to cardiac injury, which can be monitored by measuring cardiac troponin T (cTnT). We performed a nested prospective cohort study at a university level III neonatal intensive care unit. The study included 27 infants weighing between 500 and 999 g. Exclusion criteria included evidence of sepsis, use of postnatal steroids, and cardiac anomalies. Measurements included serum cTnT and echocardiogram in the first 48 hours of life. The mean serum cTnT level of the study population was 0.52 +/- 0.38 ng/ml. It was higher in those with lower Apgar scores (0.89 +/- 0.37 if 5-minute Apgar < 4 vs 0.36 +/- 0.26 ng/ml, p < 0.001) and correlated to initial base deficit (r = -0.37, p < 0.05). Infants who required inotropic support had higher cTnT levels than those who did not (0.73 +/- 0.43 vs 0.39 +/- 0.29 ng/ml, p < 0.03). cTnT concentrations did not relate to simultaneous echocardiographic measures of cardiac function. In ELBW infants, serum cTnT levels are higher than normally seen in term infants and adults, and they are higher in infants with greater perinatal stress as well as those who show evidence of cardiac dysfunction requiring pressor support.

Current opinion regarding indications for emergency department thoracotomy.

BACKGROUND: Emergency department thoracotomy (EDT) is a dramatic but rarely lifesaving intervention. Clinical variability regarding indications for EDT has yet to be quantified. Members of the Eastern and American Associations for the Surgery of Trauma were questioned by mail to evaluate which clinical and demographic factors influence the decision to perform EDT and whether physicians perform EDT in accordance with current practice guidelines. METHODS: A single mailing of an anonymous survey was sent to 1,124 surgeons to collect institutional and physician demographics as well as indications for EDT on the basis of variable mechanisms of trauma, duration of arrest, and signs of life (SOL). Statistical analysis included the Pearson and linear-by-linear association chi(2) tests, independent samples t test, and univariate and multivariate analyses of variance; p values of < 0.05 were considered significant. RESULTS: Completed surveys were received from 358 respondents. After 54 surveys were excluded that were incomplete, late, or from noneligible respondents, 304 surveys were analyzed. There were no significant differences in EDT indications among institutions of differing caseload volume, exposure to penetrating trauma, trauma level designation, American College of Surgeons verification status, or residency program affiliation. In addition, neither the respondent's position nor whether attendings versus residents performed the majority of EDTs influenced clinical decision-making. Performance criteria for EDT were liberal in comparison with established guidelines, especially for blunt trauma. The presence or recent loss of SOL influenced responses, but respondents varied greatly in their definition of SOL. CONCLUSION: A lack of agreement exists regarding the indications for EDT in multiple clinical scenarios as well as in defining SOL. Indications for EDT were liberal, especially for blunt trauma-related indications, and were determined by clinical parameters, not by physician or institutional factors. Our results suggest that clinical practice is at variance with Advanced Trauma Life Support guidelines. We recommend that practice guidelines for EDT be established on the basis of a consensus definition of SOL to allow for a more uniform and selective approach to EDT.

Control of T cell development in vivo by subdomains within the IL-7 receptor alpha-chain cytoplasmic tail.

IL-7/IL-7R signaling functions in both growth and differentiation during T cell development. In this study, we examined the extent these activities were controlled by signaling associated with distinct IL-7R alpha cytoplasmic domains by transgenic expression of wild-type or cytoplasmic deletion mutants of IL-7R alpha in the thymi of IL-7R alpha(-/-) mice. We show an essential requirement for the tyrosine-containing carboxyl-terminal T domain in restoring thymic cellularity, pro-/pre-T cell progression, and survival. In contrast, the functional differentiation of TCR alpha beta cells and the development of TCR gamma delta cells are partially independent of the T domain. Thus, separate cytoplasmic domains of the IL-7R alpha chain differentially control distinct functions during T cell development, whereas normal IL-7R-dependent thymic development requires the integrated activity of all these domains.

Thymic and intestinal intraepithelial T lymphocyte development are each regulated by the gammac-dependent cytokines IL-2, IL-7, and IL-15.

Both thymic and extrathymic T lineage development are characterized by cytokine-dependent regulation of complex proliferative, differentiative, and anti-apoptotic processes. The role of the gammac-dependent cytokines in this program has been interpreted as limited to the activity of IL-7. However, through the analysis of double knock-out mice, which lack signaling through the IL-7R and other gammac-dependent cytokines, we revealed a role for IL-15 in the production of early thymic pro-T cells. Although IL-2 does not function in the production of thymocytes, thymic restoration of IL-2R expression prevented fatal autoimmunity associated with IL-2- or IL-2R-deficient mice, suggesting that IL-2R functions non-redundantly at the level of the thymus to regulate self-reactivity. Moreover, IL-2, IL-7, and IL-15 also extend their developmental effects beyond the thymus to other sites of T lymphocyte production, including the gut. Here, their redundant and non-redundant activities are directly correlated to the development of phenotypically diverse subsets of intestinal intraepithelial lymphocytes.

Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors.

The importance of IL-2Rbeta function for immune regulation is highlighted by the severe impairment in lymphoid cell function in IL-2Rbeta-deficient mice. It has been speculated that failed IL-2/IL-2R signaling in peripheral T cells causes the associated autoimmunity, imbalanced peripheral lymphoid homeostasis, and defective T cell function. This study explored the requirement for IL-2Rbeta function in mature T lymphocytes. We show that transgenic thymic expression of the IL-2R beta-chain in IL-2Rbeta-deficient mice prevents lethal autoimmunity, restores normal production of B lymphocytes, and results in a peripheral T cell compartment that is responsive to triggering through the TCR, but not the IL-2R. The dysfunction of the IL-2R is illustrated by the near complete failure of mature T cells to proliferate to IL-2 in vitro and in vivo, to differentiate into CTL, and to up-regulate IL-2Ralpha expression. These data indicate that lymphoid homeostasis is largely maintained despite a nonfunctional IL-2R in mature T lymphocytes and suggest that IL-2Rbeta provides an essential signal during thymic development to regulate self-reactivity.

IL-2Rbeta/IL-7Ralpha doubly deficient mice recapitulate the thymic and intraepithelial lymphocyte (IEL) developmental defects of gammac-/- mice: roles for both IL-2 and IL-15 in CD8alphaalpha IEL development.

IL-7Ralpha-chain-deficient (IL-7Ralpha-/-) and common gamma chain-deficient (gammac-/-) mice both exhibit abnormal thymic and intestinal intraepithelial lymphocyte (IEL) development, but the developmental inhibition is not equivalent. In this report, we assessed whether the defects in T cell development associated with gammac-/- mice were due to currently defined gammac-dependent cytokines by cross-breeding IL-7Ralpha-/- mice to mice lacking either IL-2, IL-4, or IL-2Rbeta. IL-2/IL-7Ralpha and IL-4/IL-7Ralpha double knockout (DKO) mice demonstrated equivalent thymic development to IL-7Ralpha-/- mice, whereas IL-2Rbeta/IL-7Ralpha DKO mice, which lack IL-2, IL-7, and IL-15 signaling, displayed thymic T cell defects identical to gammac-/- mice. Collectively, these data indicate that of the gammac-dependent cytokines, only IL-7 and IL-15 contribute to the progression and production of thymic T cells. In the IEL, IL-7Ralpha-/- mice selectively lack CD8alphaalpha TCRgammadelta cells, whereas IL-2Rbeta-/- mice show a significant reduction in all CD8alphaalpha cells. IL-2-/- and IL-2/IL-7Ralpha DKO mice demonstrated a reduction in CD8alphaalpha IELs to nearly the same extent as IL-2Rbeta-/- mice, indicating that IL-2 functions in CD8alphaalpha IEL development. Moreover, IL-2Rbeta/IL-7Ralpha DKO mice lacked nearly all TCR-bearing IEL, again recapitulating the phenotype of gammac-/- mice. Thus, these data point to the importance of IL-2, IL-7, and IL-15 as the gammac-dependent cytokines essential for IEL development.

Prostaglandin E2 inhibits T cell activation-induced apoptosis and Fas-mediated cellular cytotoxicity by blockade of Fas-ligand induction.

Prostanoids exhibit both pro-apoptotic and anti-apoptotic functions depending on the maturation stage and tissue localization of target cells. Prostaglandin (PG) E2 has been shown to protect T lymphocytes from TCR-mediated activation-induced cell death, but the mechanism by which PGE2 inhibits apoptosis of T cells has not been established. We show that this protection involves the down-regulation of Fas-ligand (Fas-L) mRNA levels in T cells. Modulation of cell surface Fas-L expression by physiological concentrations of PGE2 was shown to be both anti-apoptotic as well as capable of inhibiting Fas-L-mediated cytotoxicity of Fas-transfected P815 target cells. Thus, this study provides direct evidence of the likely biological means by which PGE2 down-regulates T cell apoptosis.

Multiple gamma c-dependent cytokines regulate T-cell development.

Mutations in the common gamma chain (gamma c) of cytokine receptors account for human X-linked severe combined immunodeficiency disease. gamma c contributes to ligand binding and signaling as a component of five cytokine receptors: interleukin-2-receptor (IL-2R), IL-4R, IL-7R, IL-9R and IL-15R. Here, Thomas Malek and colleagues discuss the contribution of individual gamma c-dependent cytokines in both conventional and intraepithelial T-cell development.