The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE 2 , a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE 2 exerts its downstream effects by signaling through a class of four distinct G-proteincoupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE 2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMPdependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE 2 receptor subtype in brain that may provide a target for therapeutic intervention.

Epidemiological studies demonstrate that chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) in normal aging populations reduces the risk of developing Alzheimer's disease (AD). NSAIDs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2, which catalyze the first committed step in the synthesis of prostaglandins. These studies implicate COX-mediated inflammation as an early and potentially reversible preclinical event; however, the mechanism by which COX activity promotes development of AD has not been determined. Recent studies implicate the prostaglandin E 2 (PGE 2 ) E prostanoid subtype 2 (EP2) receptor in the development of the innate immune response in brain. Here, we report that deletion of the PGE 2 EP2 receptor in the APPSwe-PS1⌬E9 model of familial AD results in marked reductions in lipid peroxidation in aging mice. This reduction in oxidative stress is associated with significant decreases in levels of amyloid-␤ (A␤) 40 and 42 peptides and amyloid deposition. Aged APPSwe-PS1⌬E9 mice lacking the EP2 receptor harbor lower levels of ␤ C-terminal fragments, the product of ␤-site APP cleaving enzyme (BACE1) processing of amyloid precursor protein. Increases in BACE1 processing have been demonstrated in models of aging and AD and after oxidative stress. Our results indicate that PGE 2 signaling via the EP2 receptor promotes age-dependent oxidative damage and increased A␤ peptide burden in this model of AD, possibly via effects on BACE1 activity. Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD, and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD.

Background Loss-of-function null mutations R501X and 2282del4 in the skin barrier gene, filaggrin (FLG), represent the most replicated genetic risk factors for atopic dermatitis (AD). Associations have not been reported in African ancestry populations. Eczema herpeticum (ADEH) is a rare but serious complication of AD resulting from disseminated cutaneous HSV infections. Objective We aimed to determine whether FLG polymorphisms contribute to ADEH susceptibility. Methods Two common loss-of-function mutations plus nine FLG single nucleotide polymorphisms (SNPs) were genotyped in 278 European American AD patients, of whom 112 had ADEH, and 157non-atopic controls. Replication was performed on 339 African Americans. Results Significant associations were observed for both the R501X and 2282del4 mutations and AD among European Americans (P=1.46×10−5,3.87×10−5, respectively), but the frequency of the R501X mutation was three times higher (25.% vs 9%) for ADEH compared to AD without EH (odds ratio [OR]=3.4 (1.7–6.8), P=0.0002). Associations with ADEH were stronger with the combined null mutations (OR=10.1 (4.7–22.1), P=1.99×10−11). Associations with the R501X mutation were replicated in the African American population; the null mutation was absent among healthy African Americans, but present among AD (3.2%, P=0.035) and common among ADEH (9.4%; P=0.0049) patients. However, the 2282del4 mutation was absent among African American ADEH patients and rare (<1%) among healthy individuals. Conclusion The R501X mutation in the gene encoding filaggrin, one of the strongest genetic predictors of AD, confers an even greater risk for ADEH in both European and African ancestry populations, suggesting a role for defective skin barrier in this devastating condition. Clinical Implications The Filaggrin (FLG) R501X Mutation, a major risk factor for atopic dermatitis, confers a greater risk of the severe, HSV-associated complication, eczema herpeticum in diverse ethnic groups. Capsule Summary Mutations in the skin barrier function protein, filaggrin, are strong predictors of atopic dermatitis. This report demonstrates an even greater association between one of these mutations (R501X) and eczema herpeticum in ethnically diverse American populations.

Background Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. Objectives To test the hypothesis that some genes may contribute to the profound disparities in asthma. Methods We performed a genome-wide association study in two independent populations of African ancestry (935 African American asthma cases and controls from the Baltimore-Washington, D.C. area, and 929 African Caribbean asthmatics and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. Results Meta-analysis combining these two African-ancestry populations yielded three SNPs with a combined P-value <10-5 in genes of potential biological relevance to asthma and allergic disease: rs10515807, mapping to alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57×10-6); rs6052761, mapping to prion-related protein (PRNP) on chromosome 20pter-p12 (2.27×10-6); and rs1435879, mapping to dipeptidyl peptidase 10 (DPP10) on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of UK and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Conclusions Evidence for association was also examined in four additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease such as asthma in admixed populations, especially populations of African descent.