Publications

Primary abnormalities in permeability barrier function appear to underlie atopic dermatitis and epidermal trauma; a concomitant barrier dysfunction could also drive other inflammatory dermatoses, including psoriasis. Central to this outside-inside view of disease pathogenesis is the epidermal generation of cytokines/growth factors, which in turn signal downstream epidermal repair mechanisms. Yet, this cascade, if sustained, signals downstream epidermal hyperplasia and inflammation. We found here that acute barrier disruption rapidly stimulates mRNA and protein expression of epidermal vascular endothelial growth factor-A (VEGF-A) in normal hairless mice, a specific response to permeability barrier requirements because up-regulation is blocked by application of a vapor-impermeable membrane. Moreover, epidermal vegf(-/-) mice display abnormal permeability barrier homeostasis, attributable to decreased VEGF signaling of epidermal lamellar body production; a paucity of dermal capillaries with reduced vascular permeability; and neither angiogenesis nor epidermal hyperplasia in response to repeated tape stripping (a model of psoriasiform hyperplasia). These results support a central role for epidermal VEGF in the maintenance of epidermal permeability barrier homeostasis and a link between epidermal VEGF production and both dermal angiogenesis and the development of epidermal hyperplasia. Because psoriasis is commonly induced by external trauma [isomorphic (Koebner) phenomenon] and is associated with a prominent permeability barrier abnormality, excess VEGF production, prominent angiogenesis, and epidermal hyperplasia, these results could provide a potential outside-inside mechanistic basis for the development of psoriasis.

Myocardial infarction (MI) is a common complex disease with a genetic component. While several single nucleotide polymorphisms (SNPs) have been reported to be associated with risk of MI, they do not fully explain the observed genetic component of MI. We have been investigating the association between MI and SNPs that are located in genes and have the potential to affect gene function or expression. We have previously published studies that tested about 12,000 SNPs for association with risk of MI, early-onset MI, or coronary stenosis. In the current study we tested 17,576 SNPs that could affect gene function or expression. In order to use genotyping resources efficiently, we staged the testing of these SNPs in three case-control studies of MI. In the first study (762 cases, 857 controls) we tested 17,576 SNPs and found 1,949 SNPs that were associated with MI (P<0.05). We tested these 1,949 SNPs in a second study (579 cases and 1159 controls) and found that 24 SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, we tested these 24 SNPs in a third study (475 cases and 619 controls) and found that 5 SNPs in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies. The false discovery rate for this group of 5 SNPs was 0.23. Thus, we have identified 5 SNPs that merit further examination for their potential association with MI. One of these SNPs (in LPA), has been previously shown to be associated with risk of cardiovascular disease in other studies.

BACKGROUND

Expanded HIV screening efforts in the United States have increased the use of rapid HIV tests in emergency departments. The reported sensitivity and specificity of rapid HIV tests exceed 99%.

OBJECTIVE

To assess whether a reactive rapid oral HIV test result correctly identifies adults with HIV infection in the emergency department.

DESIGN

Diagnostic test performance assessment within the framework of a randomized, clinical trial.

SETTING

Brigham and Women's Hospital emergency department (Boston, Massachusetts) from 7 February to 1 October 2007.

PATIENTS

849 adults with valid rapid oral HIV test results.

INTERVENTION

Rapid HIV testing with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania). Patients with reactive rapid test results were offered enzyme-linked immunoassay, Western blot, and plasma HIV-1 RNA testing for confirmation.

MEASUREMENTS

Specificity and positive likelihood ratio.

RESULTS

39 patients had reactive results (4.6% [95% CI, 3.2% to 6.0%]). On confirmation, 5 patients were HIV-infected (prevalence, 0.6% [CI, 0.1% to 1.1%]) and 26 were non-HIV-infected (8 patients declined confirmation). The estimated rapid test specificity was 96.9% (CI, 95.7% to 98.1%). Sensitivity analyses of the true HIV status of unconfirmed cases and test sensitivity resulted in a positive likelihood ratio of 8 to 32. Western blot alone as a confirmation test provided conclusive HIV status in only 50.0% (CI, 30.8% to 69.2%) of patients at first follow-up. The addition of HIV-1 RNA testing to the confirmation protocol improved this rate to 96.2% (CI, 88.8% to 100.0%).

LIMITATION

Test sensitivity cannot be assessed because nonreactive OraQuick test results were not confirmed.

CONCLUSION

Although patients with a reactive oral OraQuick HIV screening test in the emergency department had an 8- to 32-fold increased odds of HIV infection compared with the pretest odds, the specificity of the test was lower than anticipated.