Publications

A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the beta1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure--forced expiratory volume (FEV(1)) % of predicted value. The 818T allele is associated with a clinically significant decline (-13%) in FEV(1) in both cohorts of asthmatics among males but not females (P(combined) = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the beta1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.

OBJECTIVE

Colonoscopy, the "gold standard" screening test for colorectal cancer (CRC), has known diagnostic limitations. Advances in endoscope technology have focused on improving mucosal visualisation. In addition to increased angle of view and resolution features, recent colonoscopes have non-white-light optics, such as narrow band imaging (NBI), to enhance image contrast. We aimed to study the neoplasia diagnostic characteristics of NBI, by comparing the neoplasm miss rate when the colonoscopy was performed under NBI versus white light (WL).

DESIGN

Randomised controlled trial.

SETTING

US Veterans hospital.

PATIENTS

Elective colonoscopy adults.

INTERVENTION

We randomly assigned patients to undergo a colonoscopic examination using NBI or WL. All patients underwent a second examination using WL, as the reference standard.

MAIN OUTCOME MEASURES

The primary end point was the difference in the neoplasm miss rate, and secondary outcome was the neoplasm detection rate.

RESULTS

In 276 tandem colonoscopy patients, there was no significant difference of miss or detection rates between NBI or WL colonoscopy techniques. Of the 135 patients in the NBI group, 17 patients (12.6%; 95% confidence interval (CI) 7.5 to 19.4%) had a missed neoplasm, as compared with 17 of the 141 patients (12.1%; 95% CI 7.2 to 18.6%) in the WL group, with a miss rate risk difference of 0.5% (95% CI -7.2 to 8.3). 130 patients (47%) had at least one neoplasm. Missed lesions with NBI showed similar characteristics to those missed with WL. All missed neoplasms were tubular adenomas, the majority (78%) was < or = 5 mm and none were larger than 1 cm (one-sided 95% CI up to 1%). Nonpolypoid lesions represented 35% (13/37) of missed neoplasms.

INTERPRETATION

NBI did not improve the colorectal neoplasm miss rate compared to WL; the miss rate for advanced adenomas was less than 1% and for all adenomas was 12%. The neoplasm detection rates were similar high using NBI or WL; almost a half the study patients had at least one adenoma. Clinicaltrials.gov identifier: NCT00628147.