Citations

Background— The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) demonstrated that implantable cardioverter-defibrillator (ICD) therapy reduces all-cause mortality in patients with New York Heart Association class II/III heart failure and a left ventricular ejection fraction ≤35% on optimal medical therapy. Whether ICD therapy reduced sudden death caused by ventricular tachyarrhythmias without affecting heart failure deaths in this population is unknown. Methods and Results— SCD-HeFT randomized 2521 subjects to placebo, amiodarone, or shock-only, single-lead ICD therapy. Over a median follow-up of 45.5 months, a total of 666 deaths occurred, which were reviewed by an Events Committee and initially categorized as cardiac or noncardiac. Cardiac deaths were further adjudicated as resulting from sudden death presumed to be ventricular tachyarrhythmic, bradyarrhythmia, heart failure, or other cardiac causes. ICD therapy significantly reduced cardiac mortality compared with placebo (adjusted hazard ratio, 0.76; 95% confidence interval, 0.60 to 0.95) and tachyarrhythmia mortality (adjusted hazard ratio, 0.40; 95% confidence interval, 0.27 to 0.59) and had no impact on mortality resulting from heart failure or noncardiac causes. The cardiac and tachyarrhythmia mortality reductions were evident in subjects with New York Heart Association class II but not in subjects with class III heart failure. The reduction in tachyarrhythmia mortality with ICD therapy was similar in subjects with ischemic and nonischemic disease. Compared with placebo, amiodarone had no significant effect on any mode of death. Conclusions— ICD therapy reduced cardiac mortality and sudden death presumed to be ventricular tachyarrhythmic in SCD-HeFT and had no effect on heart failure mortality. Amiodarone had no effect on all-cause mortality or its cause-specific components, except an increase in non-cardiac mortality in class III patients. Clinical Trial Registration Information— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000609.

ABSTRACT Capsular contracture is the most common and frustrating complication in women who have undergone breast implantation. Its cause and, accordingly, treatment and prevention remain to be elucidated fully. The aim of this prospective observational pilot study was to test the hypothesis that the presence of bacteria on breast implants is associated with capsular contracture. We prospectively studied consecutive patients who underwent breast implant removal for reasons other than overt infection at the Mayo Clinic from February through September 2008. Removed breast implants were processed using a vortexing/sonication procedure and then subjected to semiquantitative culture. Twenty-seven of the 45 implants collected were removed due to significant capsular contracture, among which 9 (33%) had ≥20 CFU bacteria/10 ml sonicate fluid; 18 were removed for reasons other than significant capsular contracture, among which 1 (5%) had ≥20 CFU/10 ml sonicate fluid ( P = 0.034). Propionibacterium species, coagulase-negative staphylococci, and Corynebacterium species were the microorganisms isolated. The results of this study demonstrate that there is a significant association between capsular contracture and the presence of bacteria on the implant. The role of these bacteria in the pathogenesis of capsular contracture deserves further study.

Abstract Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of ∼500 years (95% confidence interval, 425–625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted. [Cancer Res 2008;68(7):2145–53]

Abstract MMSET, identified by its fusion to the IgH locus in t(4;14)-associated multiple myeloma, possesses domains found within chromatin regulators, including the SET domain. MMSET protein is overexpressed and highly associated with chromatin in myeloma cell lines carrying t(4;14). MMSET possesses methyltransferase activity for core histone H3 lysine 4 and histone 4 lysine 20, whereas MMSET made in cells only modified H4. Segments of MMSET fused to the Gal4 DNA binding domain repressed transcription of a chromatin-embedded Gal4 reporter gene. MMSET-mediated repression was associated with increased H4K20 methylation gene and loss of histone acetylation. Consistent with this repressive activity, MMSET could form a complex with HDAC1 and HDAC2, mSin3a, and the histone demethylase LSD1, suggesting that it is a component of corepressor complexes. Furthermore, MMSET coexpression enhances HDAC1- and HDAC2-mediated repression in transcriptional reporter assays. Finally, shRNA-mediated knockdown of MMSET compromised viability of a myeloma cell line, suggesting a biologic role for the protein in malignant cell growth. Collectively, these data suggest that, by acting directly as a modifier of chromatin as well as through binding of other chromatin-modifying enzymes, MMSET influences gene expression and potentially acts as a pathogenic agent in multiple myeloma.

OBJECTIVE—The aim of this study was to determine personal characteristics and preferences that affect decision making (decisional attributes) in patients with diabetes. In particular, we were interested in relating these attributes to the choice of using aspirin to reduce cardiovascular risk. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional survey (70% response rate) of 206 diabetic patients (median age, 63 years; 42% women; 91% completed high school; median HbA1c, 8%) attending a tertiary care diabetes clinic. Patients answered a 42-question survey exploring decisional attributes. Medical records provided the source of clinical information. We evaluated sociodemographic, clinical, and decisional predictors of aspirin use. We also conducted a multivariable analysis with aspirin use as a dependent variable. RESULTS—Sixty-seven percent of patients surveyed used aspirin. Patients using aspirin were at higher risk of cardiovascular disease (odds ratio 1.4, 95% CI 1.0–2.1), knew more about the benefits of aspirin (1.9, 1.4–2.6) and less about the risks of aspirin (1.4, 1.2–1.8), and were more certain about using aspirin (0.5, 0.3–0.8) than patients not using aspirin. Patients using aspirin placed a higher value on preventing cardiovascular events than on avoiding the side effects of aspirin. Patients perceived that their diabetes provider and the American Diabetes Association had greater influence on their decision to use aspirin than family members or other patients with diabetes. CONCLUSIONS—The decisional attributes of patients with diabetes are associated with aspirin use. Decisional attributes may be the target of research and interventions to reduce underutilization to levels consistent with patient preferences.