Publications

BACKGROUND

extracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown.

METHODS

in this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus).

RESULTS

following two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis.

CONCLUSION

taken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

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.