Publications

BACKGROUND

Cyclooxygenase-2 (COX-2) inhibitors were widely prescribed in the years following their introduction, but little is known about the frequency and context of their use across different age groups.

OBJECTIVE

To determine patterns and context of COX-2 inhibitor use in younger and older adults.

DESIGN

Cross-sectional surveys conducted each year from 1998 to 2002.

PARTICIPANTS

National Ambulatory Medical Care survey, a nationally representative sample of patient visits to community-based outpatient practices.

MEASUREMENTS

New or preexisting medication use recorded at the patient visit.

RESULTS

Cyclooxygenase-2 inhibitor use rose rapidly in all age groups, particularly in elders. By 2002, COX-2 inhibitors accounted for 67% of recorded nonsteroidal anti-inflammatory drug (NSAID) uses in visits by patients age 65 and older, compared with 33% of NSAID uses in adults age 18 to 44 and 54% in adults age 45 to 64 (P<.001). Coadministration of proton pump inhibitors or misoprostol with NSAIDs was low throughout the study period in all age groups, ranging from 6.7% of all NSAID users in 1998 (the year before COX-2 inhibitors were introduced) to 8.2% in 2002 (P=.68). For both older and younger adults, use of these gastroprotective agents occurred at similar rates among persons taking COX-2 inhibitors compared with those taking nonselective NSAIDs. Among elderly NSAID users in 2001 to 2002, elders with cardiovascular disease were more likely to receive COX-2 inhibitors than those without cardiovascular disease (86% vs 66%, P<.001).

CONCLUSIONS

Cyclooxygenase-2 inhibitors were rapidly adopted among all age groups, but particularly among the elderly, where use in patients with cardiovascular disease was especially high. Use of these agents largely supplemented, rather than replaced, older forms of gastroprotective therapy. The rapid and widespread use of COX-2 inhibitors in spite of their higher cost and potential for complications provides important lessons for physicians' approach to new and highly promoted drugs.

The critical regulator of polarity, Par6, is a key member of a multi-component polarity complex that controls a variety of cellular processes such as asymmetric cell division, establishment of epithelial apico-basal polarity, and polarized cell migration. Recently, we have come to understand how regulation of the Par6 interactome by extracellular cues such as integrin and transforming growth factor beta signalling regulates cell motility and tight junction dissolution. These studies have begun to elucidate how signalling to the polarity complex might regulate pathological processes such as tumour cell invasion and metastasis.

BACKGROUND

Chromosome four of Drosophila melanogaster, known as the dot chromosome, is largely heterochromatic, as shown by immunofluorescent staining with antibodies to heterochromatin protein 1 (HP1) and histone H3K9me. In contrast, the absence of HP1 and H3K9me from the dot chromosome in D. virilis suggests that this region is euchromatic. D. virilis diverged from D. melanogaster 40 to 60 million years ago.

RESULTS

Here we describe finished sequencing and analysis of 11 fosmids hybridizing to the dot chromosome of D. virilis (372,650 base-pairs) and seven fosmids from major euchromatic chromosome arms (273,110 base-pairs). Most genes from the dot chromosome of D. melanogaster remain on the dot chromosome in D. virilis, but many inversions have occurred. The dot chromosomes of both species are similar to the major chromosome arms in gene density and coding density, but the dot chromosome genes of both species have larger introns. The D. virilis dot chromosome fosmids have a high repeat density (22.8%), similar to homologous regions of D. melanogaster (26.5%). There are, however, major differences in the representation of repetitive elements. Remnants of DNA transposons make up only 6.3% of the D. virilis dot chromosome fosmids, but 18.4% of the homologous regions from D. melanogaster; DINE-1 and 1360 elements are particularly enriched in D. melanogaster. Euchromatic domains on the major chromosomes in both species have very few DNA transposons (less than 0.4 %).

CONCLUSION

Combining these results with recent findings about RNAi, we suggest that specific repetitive elements, as well as density, play a role in determining higher-order chromatin packaging.

Smoking-related destructive lung diseases such as chronic obstructive pulmonary disease (COPD) and emphysema are a major cause of morbidity and mortality worldwide. The immediate cause of emphysema is the obliteration of alveoli that are key functional units of the lungs where gas exchange takes place. Alveolar generation/regeneration under normal and pathologic conditions is a poorly understood process, but may hold the key to treatment of human emphysema. We used suppression subtractive hybridization to identify genes that may control alveolar generation during periods of pre- and postnatal active alveolar development. P311, a putative neuronal protein originally identified for its high expression in late-stage embryonic brain, was highly differentially expressed during periods of active distal lung morphogenesis. Quantitative real-time RT-PCR showed that the expression of P311 is developmentally regulated, with peak levels occurring during saccular and alveolar formation. Intriguingly, P311 gene expression was significantly decreased in lungs of individuals with emphysema compared with control subjects. Consistent with a role for this gene in alveolar formation, inhibition of alveolization by dexamethasone treatment in vivo resulted in decreased expression of P311. Together our data suggest that P311 expression is tightly regulated during the critical periods of alveolar formation, and that under pathologic conditions, its relative absence may contribute to failure of alveolar regeneration and lead to the development of human emphysema.