Publications

The pulmonary epithelium serves as a barrier to prevent access of the inspired luminal contents to the subepithelium. In addition, the epithelium dictates the initial responses of the lung to both infectious and noninfectious stimuli. One mechanism by which the epithelium does this is by coordinating transport of diffusible molecules across the epithelial barrier, both through the cell and between cells. In this review, we will discuss a few emerging paradigms of permeability changes through altered ion transport and paracellular regulation by which the epithelium gates its response to potentially detrimental luminal stimuli. This review is a summary of talks presented during a symposium in Experimental Biology geared toward novel and less recognized methods of epithelial barrier regulation. First, we will discuss mechanisms of dynamic regulation of cell-cell contacts in the context of repetitive exposure to inhaled infectious and noninfectious insults. In the second section, we will briefly discuss mechanisms of transcellular ion homeostasis specifically focused on the role of claudins and paracellular ion-channel regulation in chronic barrier dysfunction. In the next section, we will address transcellular ion transport and highlight the role of Trek-1 in epithelial responses to lung injury. In the final section, we will outline the role of epithelial growth receptor in barrier regulation in baseline, acute lung injury, and airway disease. We will then end with a summary of mechanisms of epithelial control as well as discuss emerging paradigms of the epithelium role in shifting between a structural element that maintains tight cell-cell adhesion to a cell that initiates and participates in immune responses.

BACKGROUND

Inpatient antiarrhythmic drug initiation for atrial fibrillation is mandated for dofetilide (DF) and is often performed for sotalol (SL), particularly if proarrhythmia risk factors are present. Whether low-risk patients can be identified to safely allow outpatient initiation is unknown.

METHODS

A single-center retrospective cohort study was performed on patients initiated with DF or SL. Risk factors for adverse events (AEs), defined as any arrhythmia or electrocardiogram change requiring dose reduction or cessation, were identified.

RESULTS

Of 329 patients, 227 (69%) received SL and 102 (31%) DF. The cohort had a mean age of 63 ± 13 years; 70% of patients were male and had a baseline QTc of 440 ± 37 ms. A total of 105 AEs occurred in 92 patients: QTc prolongation or ventricular tachyarrhythmia in 70 patients (67% of AEs), bradyarrhythmias in 35 patients (33% of AEs), with some experiencing both AE types. Ventricular arrhythmias were seen in 23 patients (7%) and torsades de pointes in one (0.3%). Total AE rates were similar between drugs (P = 0.09); however, DF patients had more QTc prolongation or ventricular arrhythmias (P = 0.001). In SL patients, there were no predictors for QTc prolongation or ventricular proarrhythmia. In DF patients, higher baseline QTc interval (odds ratio = 1.64/25 ms, P = 0.01) was an independent predictor of QTc prolongation or ventricular proarrhythmias. For patients without proarrhythmia risk factors, overall AE rate was 26%.

CONCLUSIONS

In conclusion, AEs are common during DF and SL initiation but rarely severe in hospitalized inpatients. Baseline QTc predicts AEs for DF patients only and AE are common even in "low-risk" patients. These results support in-hospital drug initiation for all DF and SL patients.

PURPOSE

Recent anatomic studies have suggested that the dominant arterial supply of the patella enters through the inferior pole. Based upon these findings, we hypothesized that bone-patellar tendon-bone graft harvest can significantly diminish patellar vascularity.

METHODS

Nine matched pair cadaveric knee specimens (mean age 47.4 years) were dissected and cannulated. A single knee was selected to undergo routine graft harvest, and the contralateral knee was left intact to serve as a control. Gadolinium was injected, and magnetic resonance imaging (MRI) signal enhancement was quantified to determine differences in uptake. Each matched pair was subsequently injected with a urethane polymer compound and dissected to correlate vessel disruption with MRI findings.

RESULTS

We identified two predominating patterns of vessel entry. In one pattern, the vessel entered the inferomedial aspect (five o'clock/right, seven o'clock/left) of the patella and was disrupted by graft harvest in 2/9 (22.2 %) pairs. In the second pattern, the vessel entered further medial (four o'clock/right, eight o'clock/left) and was not disrupted (7/9, 78.8 %). The mean decrease in gadolinium uptake following disruption of the predominant vessel measured 56.2 % (range 42.6-69.5 %) compared to an average decrease of 18.3 % (range 7.1-29.1 %) when the dominant arterial supply to the inferior pole remained intact (p < 0.04).

CONCLUSION

Medial entry of the predominant vessel precluded vessel disruption. Disruption of the dominant arterial supply can result in a significant decrease in patellar vascularity. Modification of graft harvest techniques and areas of surgical dissection should be explored to minimize vascular insult. Further correlation with clinical studies/outcomes is necessary to determine a potential association between vascular insult and anterior knee pain.

The transcontinental spread of multidrug-resistant (MDR) tuberculosis is poorly characterized in molecular epidemiologic studies. We used genomic sequencing to understand the establishment and dispersion of MDR Mycobacterium tuberculosis within a group of immigrants to the United States. We used a genomic epidemiology approach to study a genotypically matched (by spoligotype, IS6110 restriction fragment length polymorphism, and mycobacterial interspersed repetitive units-variable number of tandem repeat signature) lineage 2/Beijing MDR strain implicated in an outbreak of tuberculosis among refugees in Thailand and consecutive cases within California. All 46 MDR M. tuberculosis genomes from both Thailand and California were highly related, with a median difference of 10 single-nucleotide polymorphisms (SNPs). The Wat Tham Krabok (WTK) strain is a new sequence type distinguished from all known Beijing strains by 55 SNPs and a genomic deletion (Rv1267c) associated with increased fitness. Sequence data revealed a highly prevalent MDR strain that included several closely related but distinct allelic variants within Thailand, rather than the occurrence of a single outbreak. In California, sequencing data supported multiple independent introductions of WTK with subsequent transmission and reactivation within the state, as well as a potential super spreader with a prolonged infectious period. Twenty-seven drug resistance-conferring mutations and 4 putative compensatory mutations were found within WTK strains. Genomic sequencing has substantial epidemiologic value in both low- and high-burden settings in understanding transmission chains of highly prevalent MDR strains.