Publications

Tumors arising from the supporting cells of peripheral nerve sheaths are relatively uncommon neoplasms, and as such many clinicians are unfamiliar with the details of their presentation, diagnosis and management. Further, little is known regarding the pathogenesis of these tumors, how they cause symptoms, and how to treat these symptoms. One classic symptom of peripheral nerve tumors is pain, however there has been little formal discussion regarding the significance of pain in this setting. Here we present a brief review of the clinical significance of pain, its relevance in pre-operative planning for the treatment of these tumors, and what is known regarding the molecular mechanisms of pain generation by these tumors.

RATIONALE

Circulating microparticles (MPs) are submicron membrane fragments shed from damaged or activated vascular cells. Endothelial MPs are a biological marker of dysfunctional endothelium. Vascular remodeling and endothelial dysfunction are involved in pulmonary hypertension (PH).

OBJECTIVES

We tested the hypothesis that circulating MPs are increased in patients with PH and that identifiable subgroups of MPs predict the hemodynamic severity of this condition progression.

METHODS

Patients (n = 24; age, 54 +/- 4 yr) undergoing right heart catheterization for precapillary PH without any endothelium-active vasodilator therapy participated in the study. Age- and sex-matched healthy control subjects (n = 20) were included. Endothelial (PECAM(+) [CD31(+)]/ CD41(-), VE-cadherin(+) [CD144(+)], and E-selectin(+) [CD62e(+)]), platelet (CD41(+)), leukocyte-derived (CD45(+)), and annexin V(+) MPs were measured by flow cytometry in platelet-free plasma from venous blood.

MEASUREMENTS AND MAIN RESULTS

Levels of circulating endothelial PECAM(+), VE-cadherin(+), E-selectin(+), and leukocyte-derived MPs, but not platelet and annexin V(+) MPs, were increased in subjects with PH compared with control subjects (P < 0.01 each). PECAM(+) and VE-cadherin(+) MP levels significantly correlated with mean pulmonary artery pressure (r = 0.92 and r = 0.87, respectively), pulmonary vascular resistance (r = 0.78 and r = 0.73), and mean right atrial pressure (r = 0.43, and r = 0.46) and correlated inversely with cardiac index (r = -0.59 and r = -0.52). These relationships were not observed for other MP subgroups, and persisted in multivariate analysis after adjustment for confounding factors.

CONCLUSIONS

In subjects with precapillary PH, levels of circulating endothelial and leukocyte MPs were increased compared with control subjects. In addition, levels of PECAM(+) and VE-cadherin(+), but not E-selectin(+), endothelial MPs predicted hemodynamic severity of the disease.

RATIONALE

Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.

OBJECTIVES

A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American.

METHODS

We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects.

MEASUREMENTS AND MAIN RESULTS

We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol.

CONCLUSIONS

Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.