Background— The transition from persistent to permanent atrial fibrillation (AF) is associated with increased complexity of fibrillatory conduction. We have investigated the spatial distribution of fibrillation waves and structural alterations in the atrial free walls in a goat model of AF. Methods and Results— AF was maintained for 3 weeks (short term [ST], persistent AF) or 6 months (long term [LT], permanent AF). Fibrillation patterns were assessed with epicardial mapping. The origin of fibrillation waves and sites of conduction abnormalities were more homogeneously distributed in LT than in ST goats. Histologically, the total area fraction occupied by fibrous tissue and the degree of perimysial fibrosis (separation between myocyte bundles) were not significantly different between groups. However, endomysial fibrosis (distance between myocytes within bundles) was significantly larger in LT goats, particularly in the outer millimeter of the atria. By contrast, myocyte diameters were larger in LT goats throughout the atrial walls. High-resolution optical mapping showed that epicardial wavefront expansion was slower and more anisotropic in LT than in ST goats. Finally, a mathematical model of a simplified atrial architecture confirmed the potential impact of epicardial endomysial fibrosis on AF complexity. Conclusions— Altered propagation after 6 months of AF is consistent with homogeneous structural remodeling in the outer millimeter of the atria. Loss of continuity of the epicardial layer because of endomysial fibrosis may reduce its synchronizing effect, thereby increasing the complexity of fibrillatory conduction pathways. The exact distribution of fibrosis may be more important for the occurrence of conduction disturbances than the overall quantity.

We previously identified overexpression of galectin-1 in activated tumor endothelium. Currently, the tumor vasculature is a target for therapeutic approaches. Little is known about galectin expression and regulation in the tumor vasculature. Here, we report the expression of galectin-1/-3/-8/-9 in the endothelium as determined by quantitative PCR, Western blot, flow cytometry, and immunohistochemistry. Galectin-2/-4/-12 were detectable at the mRNA level, albeit very low. Galectin-8 and -9 displayed alternative splicing. Immunohistochemistry of normal tissues revealed a broad but low expression of galectin-1 in the vasculature, whereas the expression levels and localization of the other galectins varied. Endothelial cell activation in vitro significantly increased the expression of galectin-1 (5.32 ؎ 1.97; P ‫؍‬ 0.04) and decreased the expression of both galectin-8 (0.59 ؎ 0.12; P < 0.04) and galectin-9 (0.32 ؎ 0.06; P < 0.002). Galectin-3 expression was unaltered. Although a portion of these proteins is expressed intracellularly, the membrane protein level of galectin-1/-8/-9 was significantly increased on cell activation in vitro, 6-fold (P ‫؍‬ Galectins are a family of proteins that share a binding affinity for ␤-galactoside-containing carbohydrates. Several members of this family are emerging as targets for cancer therapy. Apart from a direct role in cell transformation, their main contribution to tumor progression involves modification of the antitumor immune response and enhancement of the metastatic potential of tumor cells.1 There are several reports showing altered galectin expression profiles in tumor cells of different origin, [2][3][4] and compounds that interfere with galectin function in tumor cells are therefore considered for cancer therapy.An attractive site for therapeutic applications is the endothelium, ie, the monolayer of endothelial cells lining blood vessels. Endothelial cells in the tumor vasculature are easily accessible and less prone to become drug resistant, and disrupting the tumor endothelium results in massive death of tumor cells.5 Moreover, tumor endothelial cells express molecules that allow specific targeting independent of the tumor type eg, integrin ␣V␤3, CD44v3, and CD105.6 -9 Recently, we identified galectin-1 as a target molecule in the tumor endothelium. Activated tumor endothelial cells increase the expression of galectin-1, and ablation of its expression in vitro and in vivo results in impaired endothelial cell function and hampered tumor angiogenesis.10 Whether other galectins are also directly involved in endothelial cell biology and tumor angiogenesis is less well studied (for review, see Ref. 11). In the current study, we analyzed the expression of all known human galectins in the endothelium to get more insight in their possible function in endothelial cell biology. We show that multiple galectins and galectin isoforms are expressed by endothelial cells. Furthermore, the expression and distribution of endothelial galectins is altered on cell activation. These obser...

BackgroundExposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP).Methodology/Principal FindingsInformation on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944–45) and World War II years (1940–44), and father's employment status during the Economic Depression (1932–40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45–0.92). Further categorizing individuals by an index of ‘0–1’ ‘2–3’ or ‘4–7’ genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation (‘0–1 genes methylated’ HR = 1.01, 95%CI:0.74–1.37; ‘2–3 genes methylated’ HR = 0.83, 95% CI:0.61–1.15; ‘4–7 genes methylated’ HR = 0.72, 95% CI:0.49–1.04). No associations were observed with respect to the Economic Depression and WWII years.ConclusionsThis is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.

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