Role of Bi-Atrial Pacing In Slowing The Progression of Paroxysmal Atrial Fibrillation To Permanent Atrial Fibrillation.

Introduction: Bi-atrial lead placement combined with atrial overdrive pacing has demonstrated a reduction in percent time mode switched and mode switches per day. This retrospective analysis compared long term outcomes of patients with right atrial overdrive pacing alone (DAO) to patients having atrial overdrive with bi-atrial leads (BIA) in slowing the progression of paroxysmal atrial fibrillation (PAF) to permanent continuous atrial fibrillation (CAF). Methods: Thirty-three patients age 76.6 (+/-1.96) from our prior investigation were selected. The DAO control group (N=16) had received a standard right atrial pacing lead. The BIA group (N=17) had pacing leads placed in the right atrium and coronary sinus. Patients were followed for a mean 1217 days (+/-838). Days of CAF was classified as the date of final mode switch until analysis. Results: A total of 40,171 follow-up days were evaluated. The mean follow-up for both cohorts was 1217 days (+/-838). The DAO group consisted of 15,318 days (mean 957 +/-761) and the BIA group 24,853 days (mean 1461 +/-854). A lower total number of days were spent in CAF in the BIA group versus the DAO group, 1380 vs 2197 respectively. Corrected for follow-up duration, 5.55% days in CAF was seen in the BIA group vs. 14.34% in the DAO group which did not reach statistical significance. Conclusions: Although BIA overdrive pacing initially demonstrated reduced time in mode switch compared to DAO alone, this analysis did not detect a reduction in progression to CAF. More subjects or a longer follow up would be needed.

Platelet aggregation inhibition in patients receiving statins either fully or partially metabolized by CYP3A4.

Clopidogrel therapy is the standard for prevention of cardiovascular thrombotic events. Clopidogrel is converted to an active thiol by the cytochrome P450 CYP 3A4 and 2C19 enzymes. Recent studies suggest that statins metabolized by CYP3A4 attenuate the anti-aggregatory effect of clopidogrel. We evaluated the effect of CYP3A4-metabolized statins (atorvastatin, group 1) and partially-CYP3A4-metabolized statins (simvastatin, group 2) on platelet aggregation inhibition (PAI) when given concomitantly with clopidogrel as compared to patients who were statin naive (group 3). PAI was measured by PlateletWorks (Helena Laboratories ICHOR) using the platelet P2Y12 receptor agonist ADP (20 micromol). All patients were on clopidogrel therapy (75 mg/day). Non-responsiveness was defined as a PAI of < 35%. There was no statistical difference in mean PAI among groups; a higher prevalence of clopidogrel non-responders was noted in group 1 compared to group 3 (p=0.002). Multivariate analysis, adjusting for unequal presence of metabolic syndrome and hypertension, we found no statistical difference between groups. Our data suggests that statins, either fully or partially metabolized by CYP3A4, do not influence PAI when clopidogrel is used at 75 mg/day, even after adjusting for risk factors. We concluded that concomitant statins with clopidogrel therapy does not influence the effect of clopidogrel in PAI.

The impact of margins on outcome after hepatic resection for colorectal metastasis.

OBJECTIVE: To analyze the impact of margin width on long-term outcome after hepatic resection for colorectal metastasis. SUMMARY BACKGROUND DATA: The optimal margin width and its influence on long-term outcome after hepatic resection for colorectal metastasis are unclear. METHODS: All patients undergoing hepatic resection for colorectal metastasis from 1991 to 2003 were identified, and the prognostic influence of margin width and other clinicopathologic factors were analyzed. RESULTS: A total of 1019 patients with a clear description of margin width were included. Analysis of margin width as a continuous variable suggested the following grouping: group I, involved (n = 112, 11%); group II, <1-10 mm (n = 563, 55%); and group III, >10 mm (n = 344, 33.7%). On univariate analysis, there was a statistically significant difference in median survival between all 3 groups: group II versus group I (42 vs. 30 months, P < 0.01) and group III versus group II (55 vs. 42 months, P < 0.01). Margin width >1 cm retained statistical significance (P < 0.01) on multivariate analysis after adjusting for established risk factors. After adjustment, survival in group III was significantly better than either group I or II (P < 0.01), but there was no difference between groups I and II (P = 0.31). CONCLUSIONS: This study provides evidence that margin width of >1 cm is optimal and is an independent predictor of survival after hepatic resection for colorectal metastasis. However, subcentimeter resections are also associated with favorable outcome and should not preclude patients from undergoing resection.

De novo expression of the integrin alpha5beta1 regulates alphavbeta3-mediated adhesion and migration on fibrinogen.

Recent evidence demonstrates that interactions between different integrins that are present on the cell surface can strongly influence the adhesive function of individual receptors. In this report, we show that Chinese hamster ovary cells that express the integrin alphavbeta3 in the absence of alpha5beta1 demonstrate increased adhesion and migration on fibrinogen. Furthermore, alphavbeta3-mediated adhesion to fibrinogen is not augmented by the soluble agonist, MnCl2, suggesting that alphavbeta3 exists in a higher affinity state in these cells. De novo expression of wild-type alpha5beta1 negatively regulates alphavbeta3-mediated adhesion and migration. This effect is not seen with expression of a chimeric alpha5beta1 integrin in which the cytoplasmic portion of the alpha5 integrin subunit is replaced by the cytoplasmic portion of the alpha4 integrin. In addition, it does not require ligation of alpha5beta1 by fibronectin. Cells that express a constitutively active beta3 integrin that contains a point mutation in the conserved membrane proximal region of the cytoplasmic tail, D723R, are resistant to the effect of alpha5beta1 expression. These data provide additional evidence of "cross-talk" between the integrins alpha5beta1 and alphavbeta3, and support the idea that alpha5beta1 regulates alphavbeta3-mediated ligand binding. This provides a relevant biological mechanism whereby variations in alpha5beta1 expression in vivo may modulate activation of alphavbeta3 to influence its adhesive function.

Alpha5beta1 integrin mediates strong tissue cohesion.

Integrins and cadherins are considered to have distinct and opposing functions. Integrins are traditionally cited for their role in cell-substratum interactions, whereas cadherins are thought to mediate strong intercellular cohesion. Together, these adhesion systems play crucial roles in a wide variety of cellular and developmental processes including cell migration, morphology, differentiation and proliferation. In this manuscript we present evidence that integrins possess the ability to mediate strong intercellular cohesion when cells are grown as 3D aggregates. Much of the data elucidating the role of integrins as mediators of cell-extracellular matrix (ECM) interactions have been generated using conventional cell culture techniques in which cells are plated onto ECM-coated 2D surfaces. In vivo, cells are embedded in a 3D meshwork of ECM proteins. We hypothesized that, within this meshwork, integrin-ECM interactions may impart cohesivity to an aggregate of cells by linking adjacent cells together. To test this hypothesis, we transfected Chinese hamster ovary (CHO-B2) cells to express alpha5beta1 integrin and found that these cells formed compact, spherical aggregates. We measured aggregate cohesivity using tissue surface tensiometry, a novel technique that quantifies cell-cell cohesivity of spheroids under physiological conditions. We determined that alpha5beta1 integrin is capable of conferring strong cohesivity (sigma=8.22+/-0.68 dynes/cm) to aggregates of alpha5-integrin-transfected cells. This cohesion was found to be independent of cadherin expression and was significantly greater than the cohesivity conferred onto CHO-B2 cells transfected with N-cadherin (sigma=3.14+/-0.20 dynes/cm, P