Faculty Bibliography

OBJECTIVE: The role of proton pump inhibitors (PPIs) in suspected GERD-related chronic laryngitis (CL) is controversial. Hence, we performed a meta-analysis of the existing randomized controlled trials (RCTs) to evaluate the efficacy of PPIs in this disorder. METHODS: Data extracted from MEDLINE (1966 to August 2005), Cochrane Controlled Trials Register (1997 to August 2005), EMBASE (1980 to August 2005), ClinicalTrials.gov website, and meetings presentations (1999-2005). Published and unpublished randomized placebo-controlled trials of PPIs in suspected GERD-related CL were selected by consensus. Random effects model was utilized with standard approaches to quality assessment, sensitivity analysis, and an exploration of heterogeneity and publication bias. The primary outcome measure was defined as the proportion of patients with >or=50% reduction in self-reported laryngeal symptoms. RESULTS: Pooled data from 8 studies (N = 344, PPI 195, placebo 149; mean age 51 yr; males 55%; study duration 8-16 wk) were analyzed. No significant quantitative heterogeneity was found among the studies (chi2= 11.22, P= 0.13). Overall, PPI therapy resulted in a nonsignificant symptom reduction compared to placebo (relative risk 1.28, 95% confidence interval 0.94-1.74). No clinical predictors of PPI response were identified on meta-regression analysis done at study level. CONCLUSIONS: PPI therapy may offer a modest, but nonsignificant, clinical benefit over placebo in suspected GERD-related CL. Validated diagnostic guidelines may facilitate the recognition of those patients most likely to respond favorably to PPI treatment

Ischemia and sepsis lead to endothelial cell damage, resulting in compromised microvascular flow in many organs. Much remains to be determined regarding the intracellular structural events that lead to endothelial cell dysfunction. To investigate potential actin cytoskeletal-related mechanisms, ATP depletion was induced in mouse pancreatic microvascular endothelial cells (MS1). Fluorescent imaging and biochemical studies demonstrated a rapid and progressive increase in F-actin along with a decrease in G-actin at 60 min. Confocal microscopic analysis showed ATP depletion resulted in destruction of actin stress fibers and accumulation of F-actin aggregates. We hypothesized these actin alterations were secondary to dephosphorylation/activation of actin-depolymerizing factor (ADF)/cofilin proteins. Cofilin, the predominant isoform expressed in MS1 cells, was rapidly dephosphorylated/activated during ATP depletion. To directly investigate the role of cofilin activation on the actin cytoskeleton during ischemia, MS1 cells were infected with adenoviruses containing the cDNAs for wild-type Xenopus laevis ADF/cofilin green fluorescent protein [XAC(wt)-GFP], GFP, and the constitutively active and inactive isoforms XAC(S3A)-GFP and XAC(S3E)-GFP. The rate and extent of cortical actin destruction and actin aggregate formation were increased in ATP-depleted XAC(wt)-GFP- and XAC(S3A)-GFP-expressing cells, whereas increased actin stress fibers were observed in XAC(S3E)-GFP-expressing cells. To investigate the upstream signaling pathway of ADF/cofilin, LIM kinase 1-GFP (LIMK1-GFP) was expressed in MS1 cells. Cells expressing LIMK1-GFP protein had higher levels of phosphorylated ADF/cofilin, increased stress fibers, and delayed F-actin cytoskeleton destruction during ATP depletion. These results strongly support the importance of cofilin regulation in ischemia-induced endothelial cell actin cytoskeleton alterations leading to cell damage and microvascular dysfunction