Publications

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTI) have become increasingly common. This study's objectives were to describe the clinical spectrum of MRSA in a community health center and to determine whether the use of specific antimicrobials correlated with increased probability of clinical resolution of SSTI. A retrospective chart review of 399 sequential cases of culture-confirmed S. aureus SSTI, including 227 cases of MRSA SSTI, among outpatients at Fenway Community Health (Boston, MA) from 1998 to 2005 was done. The proportion of S. aureus SSTI due to MRSA increased significantly from 1998 to 2005 (P<0.0001). Resistance to clindamycin was common (48.2% of isolates). At the beginning of the study period, most patients with MRSA SSTI empirically treated with antibiotics received a beta-lactam, whereas by 2005, 76% received trimethoprim-sulfamethoxazole (TMP-SMX) (P<0.0001). Initially, few MRSA isolates were sensitive to the empirical antibiotic, but 77% were susceptible by 2005 (P<0.0001). A significantly higher percentage of patients with MRSA isolates had clinical resolution on the empirical antibiotic by 2005 (P=0.037). Use of an empirical antibiotic to which the clinical isolate was sensitive was associated with increased odds of clinical resolution on empirical therapy (odds ratio=5.91), controlling for incision and drainage and HIV status. MRSA now accounts for the majority of SSTI due to S. aureus at Fenway, and improved rates of clinical resolution on empirical antibiotic therapy have paralleled increasing use of empirical TMP-SMX for these infections. TMP-SMX appears to be an appropriate empirical antibiotic for suspected MRSA SSTI, especially where clindamycin resistance is common.

BACKGROUND

Persons of lower socioeconomic status have greater cardiovascular risk than those of higher socioeconomic status. However, the mechanism through which socioeconomic status affects cardiovascular disease (CVD) is uncertain. Virtually no data are available that examine the prospective association between novel inflammatory and hemostatic CVD risk indicators, socioeconomic status, and incident CVD events.

METHODS AND RESULTS

We assessed the relationship between 2 indicators of socioeconomic status (education and income), traditional and novel CVD risk factors (high sensitivity C-reactive protein, soluble intercellular adhesion molecule-1, fibrinogen, and homocysteine), and incident CVD events among 22,688 apparently healthy female health professionals participating in the Women's Health Study. These women were followed up for 10 years for the development of myocardial infarction, ischemic stroke, coronary revascularization, and cardiovascular death. More educated women were less likely to be smokers; had a lower prevalence of hypertension, diabetes, and obesity; and were more likely to participate in vigorous physical activity than less educated women. At baseline, median total cholesterol, low-density lipoprotein, triglyceride, C-reactive protein, intercellular adhesion molecule-1, fibrinogen, and homocysteine levels for women in 5 categories of education (< 2 years of nursing education, 2 to < 4 years of nursing education, a bachelor's degree, a master's degree, and a doctoral degree) and 6 categories of income [< or = 19,999 dollars, 20,000 dollars to 29,999 dollars, 30,000 dollars to 39,999 dollars, 40,000 dollars to 49,999 dollars, 50,000 dollars to 99,999 dollars, and > or = 100,000 dollars) decreased progressively with increasing education or income levels (all P<0.001), whereas an opposite pattern was observed for high-density lipoprotein (P<0.001). Overall, in age-adjusted Cox proportional hazards models, the relative risk of incident CVD events decreased with increasing education (1.0, 0.7, 0.5, 0.4, and 0.5; P for trend <0.001) and income (1.0, 1.0, 0.9, 0.7, 0.6, and 0.4; P for trend <0.001) categories. In multivariate models that assessed the impact of traditional and novel CVD risk factors on the relationship between education/income and CVD events, the relative hazard of incident CVD associated with a 1-category-higher level of education changed from 0.79 in age- and race-adjusted analysis to 0.89 in fully adjusted analysis. The 11% lower risk per 1 category of education remained significant (P for trend=0.006), suggesting that controlling for both novel and traditional risk factors could not explain the protective effect of education. A similar analysis for income revealed that its relationship with CVD events was explained largely by these noted risk factors.

CONCLUSIONS

In this prospective analysis, we observed a decrease in incident CVD events with increasing levels of education and income. In contrast to the relationship between income and CVD events, the relationship of CVD events with education was explained only partially by traditional and novel risk factors for CVD.

The expression of self-antigen in the thymus is believed to be responsible for the deletion of autoreactive T lymphocytes, a critical process in the maintenance of unresponsiveness to self. The Autoimmune regulator (Aire) gene, which is defective in the disorder autoimmune polyglandular syndrome type 1, has been shown to promote the thymic expression of self-antigens. A clear link, however, between specific thymic self-antigens and a single autoimmune phenotype in this model has been lacking. We show that autoimmune eye disease in aire-deficient mice develops as a result of loss of thymic expression of a single eye antigen, interphotoreceptor retinoid-binding protein (IRBP). In addition, lack of IRBP expression solely in the thymus, even in the presence of aire expression, is sufficient to trigger spontaneous eye-specific autoimmunity. These results suggest that failure of thymic expression of selective single self-antigens can be sufficient to cause organ-specific autoimmune disease, even in otherwise self-tolerant individuals.