Publications

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.

CONTEXT

Both comorbid conditions and functional measures predict mortality in older adults, but few prognostic indexes combine both classes of predictors. Combining easily obtained measures into an accurate predictive model could be useful to clinicians advising patients, as well as policy makers and epidemiologists interested in risk adjustment.

OBJECTIVE

To develop and validate a prognostic index for 4-year mortality using information that can be obtained from patient report.

DESIGN, SETTING, AND PARTICIPANTS

Using the 1998 wave of the Health and Retirement Study (HRS), a population-based study of community-dwelling US adults older than 50 years, we developed the prognostic index from 11,701 individuals and validated the index with 8009. Individuals were asked about their demographic characteristics, whether they had specific diseases, and whether they had difficulty with a series of functional measures. We identified variables independently associated with mortality and weighted the variables to create a risk index.

MAIN OUTCOME MEASURE

Death by December 31, 2002.

RESULTS

The overall response rate was 81%. During the 4-year follow-up, there were 1361 deaths (12%) in the development cohort and 1072 deaths (13%) in the validation cohort. Twelve independent predictors of mortality were identified: 2 demographic variables (age: 60-64 years, 1 point; 65-69 years, 2 points; 70-74 years, 3 points; 75-79 years, 4 points; 80-84 years, 5 points, >85 years, 7 points and male sex, 2 points), 6 comorbid conditions (diabetes, 1 point; cancer, 2 points; lung disease, 2 points; heart failure, 2 points; current tobacco use, 2 points; and body mass index <25, 1 point), and difficulty with 4 functional variables (bathing, 2 points; walking several blocks, 2 points; managing money, 2 points, and pushing large objects, 1 point. Scores on the risk index were strongly associated with 4-year mortality in the validation cohort, with 0 to 5 points predicting a less than 4% risk, 6 to 9 points predicting a 15% risk, 10 to 13 points predicting a 42% risk, and 14 or more points predicting a 64% risk. The risk index showed excellent discrimination with a cstatistic of 0.84 in the development cohort and 0.82 in the validation cohort.

CONCLUSION

This prognostic index, incorporating age, sex, self-reported comorbid conditions, and functional measures, accurately stratifies community-dwelling older adults into groups at varying risk of mortality.

OBJECTIVE

To investigate the association between the introduction of HAART and invasive pneumococcal disease (IPD) in HIV-infected patients.

METHODS

Incidence of IPD was determined from 1990 to 2003 in a cohort of HIV-infected individuals and a nested case-control study assessed risk factors of IPD.

RESULTS

There were 72 cases over 19,020 person-years of follow-up (overall IPD rate, 379/100,000 person-years). In the calendar periods 1990-1995, 1995-1998, and 1998-2003, the IPD incidence per 100,000 person-years was 279 [95% confidence interval (CI), 150-519], 377 (95% CI, 227-625) and 410 (95% CI, 308-545), respectively (P = 0.516). CD4 cell count < 200 cells/microl [odds ratio (OR), 3.0; 95% CI, 1.2-7.6), HIV RNA > 50,000 copies/ml (OR, 2.8; 95% CI, 1.2-6.5), hepatitis C (OR, 4.9; 95% CI, 1.7-14.9), serum albumin (OR, 0.1; 95% CI, 0.04-0.5), injection drug use in women (OR, 3.8; 95% CI, 1.6-8.8), and education beyond high school (OR, 0.2; 95% CI, 0.05-0.8) were significantly associated with IPD in multivariate analysis. No treatment factor, including HAART (OR, 0.7; 95% CI, 0.3-1.5) and pneumococcal vaccination (OR, 0.9; 95% CI, 0.5-1.6), was associated with IPD.

CONCLUSIONS

IPD incidence did not change significantly during the widespread dissemination of HAART in this cohort. IPD risk was associated with several sociodemographic and clinical factors.