Objective To assess whether African-Americans are at increased risk of developing peripartum cardiomyopathy. Background Peripartum cardiomyopathy is a heart disease of unknown cause that affects young women, often with devastating consequences. The frequency of peripartum cardiomyopathy varies markedly between African and non-African regions. Methods A case-control study was performed at a regional center that provides medical care to a racially heterogeneous population. For each case, 3 normal control patients were randomly selected that delivered babies within the same month. Results African-American women had a 15.7-fold higher relative risk of peripartum cardiomyopathy than non-African-Americans (odds ratio (OR) 15.7, 95% confidence interval (CI): 3.5–70.6). Other significant univariate risk factors were hypertension (OR 10.8, CI: 2.6–44.4), being unmarried (OR 4.2, 95% CI: 1.4–12.3), and > 2 previous pregnancies (OR 2.9, CI: 1.1–7.4). African-American ethnicity remained a significant risk factor for peripartum cardiomyopathy when other risk factors were considered in multivariable (OR 31.5, CI: 3.6–277.6) and stratified analyses (OR range 12.9–29.1, p<0.001). Although the frequency of peripartum cardiomyopathy (185 per 100,000 deliveries) at this center was higher than previous U.S. reports, it was comparable to the frequency in countries with more women of African descent (100–980 per 100,000). Analysis of other U.S. studies confirmed that the frequency of peripartum cardiomyopathy was significantly higher in African-American women. Conclusions African-American women have significantly higher odds of developing peripartum cardiomyopathy that could not be explained by several other factors. Further research will be necessary to determine the potential environmental and/or genetic factors associated with African descent that confer this risk.

Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number of strategies to inhibit ATM-and ATR-dependent signaling pathways during infection. Recent work suggests that the Ad5 E4orf3 protein prevents ATR activation through its ability to mislocalize the MRN complex. Here we provide evidence to indicate that Ad12 has evolved a different strategy from Ad5 to inhibit ATR. We show that Ad12 utilizes a CUL2/RBX1/elongin C-containing ubiquitin ligase to promote the proteasomal degradation of the ATR activator protein topoisomerase-IIβ-binding protein 1 (TOPBP1). Ad12 also uses this complex to degrade p53 during infection, in contrast to Ad5, which requires a CUL5-based ubiquitin ligase. Although Ad12-mediated degradation of p53 is dependent upon both E1B-55K and E4orf6, Ad12-mediated degradation of TOPBP1 is solely dependent on E4orf6. We propose that Ad12 E4orf6 has two principal activities: to recruit the CUL2-based ubiquitin ligase and to act as substrate receptor for TOPBP1. In support of the idea that Ad12 E4orf6 specifically prevents ATR activation during infection by targeting TOPBP1 for degradation, we demonstrate that Ad12 E4orf6 can inhibit the ATR-dependent phosphorylation of CHK1 in response to replication stress. Taken together, these data provide insights into how Ad modulates ATR signaling pathways during infection.DNA damage | cullin-RING ubiquitin ligases | DNA damage | proteasome

The ability of adenovirus early region proteins, E1B-55K and E4orf6, to usurp control of cellular ubiquitin ligases and target proteins for proteasome-dependent degradation during infection is well established. Here we show that the E4 gene product, E4orf3 can, independently of E1B-55K and E4orf6, target the transcriptional corepressor transcriptional intermediary factor 1␥ (TIF1␥) for proteasome-mediated degradation during infection. Initial mass spectrometric studies identified TIF1 family members-TIF1␣, TIF1␤, and TIF1␥-as E1B-55K-binding proteins in both transformed and infected cells, but analyses revealed that, akin to TIF1␣, TIF1␥ is reorganized in an E4orf3-dependent manner to promyelocytic leukemia protein-containing nuclear tracks during infection. The use of a number of different adenovirus early region mutants identified the specific and sole requirement for E4orf3 in mediating TIF1␥ degradation. Further analyses revealed that TIF1␥ is targeted for degradation by a number of divergent human adenoviruses, suggesting that the ability of E4orf3 to regulate TIF1␥ expression is evolutionarily conserved. We also determined that E4orf3 does not utilize the Cullin-based ubiquitin ligases, CRL2 and CRL5, or the TIF1␣ ubiquitin ligase in order to promote TIF1␥ degradation. Further studies suggested that TIF1␥ possesses antiviral activity and limits adenovirus early and late gene product expression during infection. Indeed, TIF1␥ knockdown accelerates the adenovirus-mediated degradation of MRE11, while TIF1␥ overexpression delays the adenovirus-mediated degradation of MRE11. Taken together, these studies have identified novel adenovirus targets and have established a new role for the E4orf3 protein during infection.H uman adenoviruses (Ad) are small, nonenveloped viruses with a linear double-stranded DNA genome and are classified into species A to F according to various criteria (7). Since the observation that Ad12 could induce tumors in newborn rodents, Ad has served as a reliable model for dissecting the molecular basis of the key cellular signaling pathways that underlie the transformation process (28,33,69,70). Studies investigating the roles of the Ad early region proteins in both Ad-transformed and Adinfected cells have led to key advances in the understanding of basic cellular processes and how Ad usurps control of these pathways in order to promote viral replication (8,33,67).The Ad early region proteins E1B-55K, E4orf3, and E4orf6 have a complex inter-relationship and serve together to regulate RNA processing, late viral mRNA nuclear export, the shutoff of host-cell protein synthesis, and neutralization of the host cell DNA damage response during infection (4,29,57,61,67,73). They can also function synergistically and cooperate with E1A to promote Ad-induced cellular transformation (47-49). It is perhaps not surprising, therefore, that they share many common functions. For instance, E1B-55K interacts directly with p53 to repress transcriptional activity and also promotes p53 sumoylation and targeting t...

Pharmacologic stress agents (dipyridamole, adenosine and dobutamine) allow virtually all patients to be safely assessed for ischemic heart disease. These agents have mild but significant side effects, mandating a thorough knowledge of indications, contraindications, side effects and management before their use. Adjunctive exercise improves image quality in vasodilator pharmacologic myocardial perfusion imaging. Diabetics, especially women, have a much higher cardiac event rate than nondiabetics for an equal amount of ischemia. They also have a higher incidence of asymptomatic ischemia. There is growing support for screening with myocardial perfusion imaging (MPI) for asymptomatic ischemia in diabetics. The ability of MPI to identify hypocontractile but viable myocardium, thus predicting improvement in myocardial function after revascularization, is one of the most powerful uses of the modality. Vasodilator MPI should be used as the initial test in patients with left bundle branch block or paced ventricular rhythm, even if they are able to exercise.

The pattern of encircling reperfusion on the stress-minus-delay bull's-eye map can improve the interpreter's confidence and sensitivity without significantly compromising specificity for identifying true myocardial perfusion defects.