Publications

OBJECTIVE

To explore the extent to which sex-specific result (SSR) reporting appears in recently published cardiovascular studies.

METHODS

All original adult cardiovascular clinical trials published in Annals of Internal Medicine, Archives of Internal Medicine, Journal of the American Medical Association, The New England Journal of Medicine, Journal of the American College of Cardiology, The American Journal of Cardiology, and Circulation from July 1 through December 31, 2004, were reviewed. Sex-specific result reporting was defined as presenting primary outcomes for women in a format to allow the data to be abstracted for use in a meta-analysis.

RESULTS

Of the 645 studies reviewed, 17 were excluded because they were appropriately single-sex trials. Of the remaining 628 studies, only 153 (24%) provided SSRs. The percentage of studies reporting SSRs was 37% (23/62) for general medical journals and 23% (130/566) for cardiovascular journals (P = .10). Among National Institutes of Health (NIH)-sponsored research, 31 (51%) of 61 trials analyzed outcomes by sex compared with 125 (22%) of 567 trials not sponsored by the NIH (P < .01).

CONCLUSION

Only a few current cardiovascular trials provide sex-specific data. Sex differences remain poorly understood, and this deficiency limits our ability to optimize medical care for both sexes. The stipulation that SSRs be investigated has led to significantly more SSR reporting in NIH-funded research. A parallel mandate by journal editors that requires authors to provide sex-specific data and analysis may help to bridge this knowledge gap.

BACKGROUND

Increased plasminogen activator inhibitor-1 (PAI-1) concentrations are found in bronchoalveolar lavage (BAL) fluids from patients with ventilator-associated pneumonia or acute respiratory distress syndrome. The authors hypothesized that PAI-1 concentrations were associated with increased mortality in patients with either Pseudomonas aeruginosa-induced ventilator-associated pneumonia or tracheobronchial colonization.

METHODS

In a prospective cohort study, daily aspirates from intubated patients were cultured for P. aeruginosa. Positive patients had blind BAL (bBAL) that was processed for biomarker concentrations. Secretion of type III secretion cytotoxins were also analyzed from the P. aeruginosa strains.

RESULTS

Thirty-three patients were enrolled. Ten of the 33 patients died. bBAL PAI-1 concentrations were significantly increased in nonsurvivors compared with survivors (31.7 vs. 3.4 ng/ml, P = 0.001 for hospital mortality; 35.9 vs. 4.7 ng/ml, P = 0.02 for 28-day mortality). Even when acute respiratory distress syndrome patients were excluded, there was a significant difference between the survivors and nonsurvivors for bBAL PAI-1 concentrations (P = 0.005). Eighty-three percent of P. aeruginosa strains isolated from patients with high concentrations of bBAL PAI-1 also had strains that secreted cytotoxins.

CONCLUSIONS

PAI-1 concentrations in bBALs correlated with mortality in ventilated patients with positive cultures for P. aeruginosa. Elevated bBAL PAI-1 concentrations also correlated with the secretion of type III exotoxins by P. aeruginosa.

APOBEC3G (A3G) is a potent antiretroviral deoxycytidine deaminase that, when incorporated into HIV virions, hypermutates nascent viral DNA formed during reverse transcription. HIV Vif counters the effect of A3G by depleting intracellular stores of the enzyme, thereby blocking its virion incorporation. Through pulse-chase analyses, we demonstrate that virion A3G is mainly recruited from the cellular pool of newly synthesized enzyme compared to older "mature" A3G already residing in high-molecular-mass RNA-protein complexes. Virion-incorporated A3G forms a large complex with viral genomic RNA that is clearly distinct from cellular HMM A3G complexes, as revealed by both gel filtration and biochemical fractionation. Unexpectedly, the enzymatic activity of virion-incorporated A3G is lost upon its stable association with HIV RNA. The activity of the latent A3G enzyme is ultimately restored during reverse transcription by the action of HIV RNase H. Degradation of the viral genomic RNA by RNase H not only generates the minus-strand DNA substrate targeted by A3G for hypermutation but also removes the inhibitory RNA bound to A3G, thereby enabling its function as a deoxycytidine deaminase. These findings highlight an unexpected interplay between host and virus where initiation of antiviral enzymatic activity is dependent on the action of an essential viral enzyme.

APOBEC3G (A3G), a deoxycytidine deaminase, is a powerful host antiretroviral factor that can restrict HIV-1 infection. This restriction is counteracted by the HIV-1 virion infectivity factor (Vif) protein, whose activity culminates in depletion of A3G from infected cells. In the absence of Vif, viruses encapsidate A3G, which acts in part to mutate viral DNA formed during reverse transcription upon subsequent infection of a new cell. Cellular A3G also functions as a post-entry restriction factor for HIV in resting CD4 T cells, where it resides in a low molecular mass form. Unfortunately, this barrier is forfeited when CD4 T cells are activated because A3G is recruited into inactive high molecular mass ribonucleoprotein complexes. In addition to restricting HIV, A3G and related deaminases may counter other retroviruses and protect the cell from endogenous mobile retroelements. Understanding A3G complex assembly and its interplay with HIV Vif may make possible future development of a new class of HIV therapeutic agents.

During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. Here we demonstrate that tumor necrosis factor (TNF) and interleukin 1 (IL-1), but not IL-6, decrease the expression of retinoid X receptor alpha (RXRalpha), peroxisome proliferator-activated receptor alpha (PPARalpha), PPARgamma, liver X receptor alpha (LXRalpha), and coactivators PPARgamma coactivator 1alpha (PGC-1alpha), PGC-1beta, and steroid receptor coactivator 1 (SRC-1) in Hep3B human hepatoma cells. In addition, treatment of mice with TNF and IL-1 also decreased RXRalpha, PPARalpha, PPARgamma, LXRalpha, and PGC-1alpha messenger RNA (mRNA) levels in the liver. These decreases were accompanied by reduced binding of nuclear extracts to RXR, PPAR, and LXR response elements and decreased luciferase activity driven by PPAR and LXR response elements. In addition, the mRNA levels of proteins regulated by PPARalpha (carnitine palmitoyltransferase 1alpha) and LXR (sterol regulatory element binding protein) were decreased in Hep3B cells treated with TNF or IL-1. Finally, using constructs of the LXRalpha promoter or the PGC-1alpha promoter linked to luciferase, we were able to demonstrate that a decrease in transcription contributes to the reduction in mRNA levels of nuclear hormone receptors and coactivators. Thus, our results suggest that decreased expression of nuclear hormone receptors RXRalpha, PPARalpha, PPARgamma, and LXRalpha, as well as coactivators PGC-1alpha, PGC-1beta, and SRC-1 may contribute to the cytokine-induced alterations in hepatic lipid metabolism during the acute phase response.

PURPOSE OF REVIEW

Airway epithelial surface signaling is provided by epidermal growth factor receptor (EGFR) phosphorylation, resulting in innate immune responses. Here the focus is the EGFR cascades leading to immune mucin responses. The review is timely because recent discoveries implicate these pathways in multiple innate immune defenses in addition to mucin production.

RECENT FINDINGS

EGFR activation causes mucin production and inhibition prevents mucin production by multiple stimuli. The receptors and their epithelial-bound proligands are examined. Proteases cleave and release soluble ligand, which then activates EGFR. A surface metalloprotease, tumor necrosis factor alpha-converting enzyme (TACE), modulates proligand release (and thus EGFR activation). TACE is activated by reactive oxygen species, which can be produced by a novel molecule, dual oxidase-1, which provides reactive oxygen species for TACE cleavage. Upstream of dual oxidase-1 are epithelial receptors that receive messages from inhaled irritants and stimulate the dual oxidase-1-TACE-ligand-EGFR cascade.

SUMMARY

The EGFR surface signaling pathways are reviewed, with the focus on mucin production, involving human airway epithelial cultures and animal studies, including relevant studies of asthma in humans. Future studies may broaden the innate defenses and utilize these surface signaling pathways in various epithelia, with a variety of pathophysiologic stimuli, with the ultimate aim of examining these pathways in inflammatory diseases.

Induction of primary B cell responses requires the presence of Ag and costimulatory signals by T cells. Innate signals further enhance B cell activation. The precise nature and kinetics of such innate immune signals and their functional effects are unknown. This study demonstrates that influenza virus-induced type I IFN is the main innate stimulus affecting local B cells within 48 h of infection. It alters the transcriptional profile of B cells and selectively traps them in the regional lymph nodes, presumably via up-regulation of CD69. Somewhat paradoxically, innate B cell stimulation inhibited the ability of regional lymph node B cells to clonally expand following BCR-mediated stimulation. This inhibition was due to IFNR-signaling independent B cell intrinsic, as well as IFNR-dependent B cell extrinsic, regulation induced following influenza infection. IFNR-mediated signals also reduced B cell migration to various chemotactic agents. Consistent with the lack of responsiveness to CCR7 ligands, unaltered or reduced expression of MHC class II and genes associated with MHC class II Ag processing/presentation and CD40, B cells were unable to induce proliferation of naive CD4 T cells. Instead, they showed increased expression of a subset of nonclassical MHC molecules that facilitate interaction with gammadelta T cells and NK T cells. We conclude that type I IFN is the main "third" B cell signal following influenza infection causing early trapping of B cells in regional lymph nodes and, at a time when cognate T cell help is rare, enhancing their propensity to interact with innate immune cells for noncognate stimulation.

Four new compounds, belonging to the tetranortriterpenoid family, named dysoxylins A-D (1-4), isolated from Dysoxylum gaudichaudianum, were found to exhibit potent antiviral activity against respiratory syncytial virus (RSV). These structures were determined by NMR spectroscopy and mass spectrometry and were shown to have anti-RSV EC50 activities in the range 1.0-4.0 microg/mL in cytopathic effect inhibition and plaque reduction assays.

T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.