Publications

1,25-dihydroxyvitamin D, through association with its cognate nuclear receptor, has been shown to have important effects in the cardiovascular and renal systems. We have shown previously that the liganded vitamin D receptor (VDR) inhibits hypertrophy and expression of hypertrophy-sensitive genes (i.e. those encoding atrial natriuretic peptide [ANP], brain natriuretic peptide and alpha skeletal actin) in neonatal cardiac myocytes. In the present study we confirm a time-, ligand- and retinoid X receptor-dependent, VDR-mediated suppression of human ANP gene promoter activity. Conventional deletion analysis demonstrated that the promoter region positioned between -217 and -104 is required for the VDR-dependent suppression of the hANP promoter. Mutation of two functional CArG elements, including one located within this critical region, failed to reverse the suppression. We found no evidence that the liganded VDR is capable of associating directly with regulatory elements positioned between -217 and -104. We conclude that the inhibition may arise from protein-protein interactions between the liganded VDR and stimulatory transcription factors that bind in this region.

The epsilon isoform of protein kinase C (PKCepsilon) has emerged as a critical second messenger in sensitization toward mechanical stimulation in models of neuropathic (diabetes, alcoholism, and cancer therapy) as well as acute and chronic inflammatory pain. Signaling pathways leading to activation of PKCepsilon remain unknown. Recent results indicate signaling from cAMP to PKC. A mechanism connecting cAMP and PKC, two ubiquitous, commonly considered separate pathways, remains elusive. We found that, in cultured DRG neurons, signaling from cAMP to PKCepsilon is not mediated by PKA but by the recently identified cAMP-activated guanine exchange factor Epac. Epac, in turn, was upstream of phospholipase C (PLC) and PLD, both of which were necessary for translocation and activation of PKCepsilon. This signaling pathway was specific to isolectin B4-positive [IB4(+)] nociceptors. Also, in a behavioral model, cAMP produced mechanical hyperalgesia (tenderness) through Epac, PLC/PLD, and PKCepsilon. By delineating this signaling pathway, we provide a mechanism for cAMP-to-PKC signaling, give proof of principle that the mitogen-activated protein kinase pathway-activating protein Epac also stimulates PKC, describe the first physiological function unique for the IB4(+) subpopulation of sensory neurons, and find proof of principle that G-protein-coupled receptors can activate PKC not only through the G-proteins alpha(q) and betagamma but also through alpha(s).

BACKGROUND

Fluoroquinolones are widely prescribed in hospitals and the community. Previous studies have shown associations between fluoroquinolone use and isolation of fluoroquinolone-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). We performed an ecologic-level study to determine whether variability in hospital percentages of fluoroquinolone-resistant E. coli and MRSA were associated with fluoroquinolone use in hospitals and their surrounding communities.

METHODS

We measured fluoroquinolone use in 17 US hospitals and their surrounding communities in the year 2000. Data on fluoroquinolone use in hospitals was electronically extracted from billing data. Data on fluoroquinolone use in communities was obtained from IMS health data for all prescriptions filled in pharmacies within a 16-km radius of each hospital. We used hospital antibiograms to determine the percentage of isolates that were fluoroquinolone-resistant E. coli and MRSA, and we performed linear regression to determine the relationship between percentage of resistant isolates and fluoroquinolone use in hospitals and their surrounding communities.

RESULTS

There was a significant association between total fluoroquinolone use within hospitals and percentage of S. aureus isolates that were MRSA (r=0.77; P=.0003) and between total fluoroquinolone use in the community and percentage of E. coli isolates that were fluoroquinolone-resistant E. coli (r=0.68; P=.003). Population density within the 16-km radius also correlated with MRSA percentage (r=0.57; P=.015) and fluoroquinolone-resistant E. coli percentage (r=0.85; P=.002), but associations between total fluoroquinolone use and resistance remained significant after adjustment for population density.

CONCLUSIONS

In this ecologic analysis, we found associations between fluoroquinolone use in hospitals and methicillin resistance in S. aureus and between fluoroquinolone use in communities and fluoroquinolone resistance in E. coli in hospitals. Antimicrobial use in hospitals and communities may have different relative importance with regard to resistance in different pathogens encountered in hospitals.

BACKGROUND

Prospective data defining the clinical course in idiopathic pulmonary fibrosis (IPF) are sparse.

OBJECTIVE

To analyze the clinical course of patients with mild to moderate IPF.

DESIGN

Analysis of data from the placebo group of a randomized, controlled trial evaluating interferon-gamma1b.

SETTING

Academic and community medical centers.

PATIENTS

168 patients in the placebo group of a trial evaluating interferon-gamma1b.

MEASUREMENTS

Measures of physiology and dyspnea assessed at 12-week intervals; hospitalizations; and the pace of deterioration and cause of death over a median period of 76 weeks.

RESULTS

Physiologic variables changed minimally during the study. However, 23% of patients required hospitalization for a respiratory disorder and 21% died. Idiopathic pulmonary fibrosis was the primary cause of death in 89% of patients who died, and an apparent acute clinical deterioration preceded death in 47% of these patients.

LIMITATIONS

The instrument used to define the pace of deterioration and cause of death was applied retrospectively.

CONCLUSIONS

Recognition of the common occurrence of acute fatal deterioration in patients with mild to moderate IPF has important implications for monitoring patients and supports early referral for lung transplantation.