Citations

Background— Aortic root remodeling in adulthood is known to be associated with cardiovascular outcomes. However, there is a lack of longitudinal data defining the clinical correlates of aortic root remodeling over the adult life course. Methods and Results— We used serial routine echocardiograms in participants of the Framingham Heart Study to track aortic root diameter over 16 years in mid to late adulthood and to determine its short-term (4 years; n=6099 observations in 3506 individuals) and long-term (16 years; n=14 628 observations in 4542 individuals) clinical correlates by multilevel modeling. Age, sex, body size, and blood pressure were principal correlates of aortic remodeling in both short- and long-term analyses (all P ≤0.01). Aortic root diameter increased with age in both men and women but was larger in men at any given age. Each 10-year increase in age was associated with a larger aortic root (by 0.89 mm in men and 0.68 mm in women) after adjustment for body size and blood pressure. A 5-kg/m 2 increase in body mass index was associated with a larger aortic root (by 0.78 mm in men and 0.51 mm in women) after adjustment for age and blood pressure. Each 10-mm Hg increase in pulse pressure was related to a smaller aortic root (by 0.19 mm in men and 0.08 mm in women) after adjustment for age and body size. Conclusions— These longitudinal community-based data show that aortic root remodeling occurs over mid to late adulthood and is principally associated with age, sex, body size, and blood pressure. The underlying basis for these differences and implications for the development of cardiovascular events deserve further study.

Realizing education and awareness are paramount in making clinical trials available, the authors sought to evaluate a statewide navigation service to identify how it might improve cancer clinical trial accessibility in Florida for physicians and patients.

ABSTRACT Since some strains of Brucella species may require carbon dioxide for growth, a multilaboratory study was conducted to compare broth microdilution susceptibility results using ambient air (AA) and 5% CO 2 incubation conditions. Six antimicrobial agents were tested against 39 Brucella isolates. Aminoglycoside MICs tended to be 1 log 2 dilution higher in CO 2 than in AA; tetracycline-class MICs to be 1 log 2 dilution lower in CO 2 .

Background— Better insight into the psychosocial factors associated with prehospital delays in seeking care for acute coronary syndromes is needed to inform the design of future interventions. Delay in presenting for care after the onset of symptoms is common, limits the potential benefit of acute reperfusion, and has not been reduced by interventions tested thus far. Methods and Results— Seven hundred ninety-six patients with suspected ischemic heart disease scheduled for clinically indicated imaging stress tests completed questionnaires concerning psychological distress and attachment styles (worthiness to receive care, trustworthiness of others to provide care). The primary dependent variable for this study was response to a question from the rapid early action for coronary treatment trial concerning intention to “wait until very sure” before seeking care for a possible “heart attack.” Responses to this question were strongly associated with actual emergency department-reported and self-reported care delay in the rapid early action for coronary treatment trial. In multivariable ordinal regression models, a more negative view of the trustworthiness of others, greater physical limitations from angina, and no previous revascularization were independently associated with increased intention to wait to seek care for a myocardial infarction. Intention to wait was not associated with inducible ischemia or self-perceived risk of myocardial infarction. Conclusions— Intention to delay seeking care for acute coronary syndromes is associated with a patient’s view of the trustworthiness of others, previous experience with revascularization, and functional limitations, even after adjustment for objective and perceived acute coronary syndromes risk. These findings provide insight into novel factors contributing to longer delay times and may inform future interventions to reduce delay time.

Abstract The DNA cross-linking agents cisplatin and oxaliplatin are widely used in the treatment of human cancer. Lesions produced by these agents are widely known to activate the G1 and G2 cell cycle checkpoints. Less is known about the role of the intra–S-phase checkpoint in the response to these agents. In the present study, two different cell lines expressing a dominant-negative kinase dead (kd) version of the ataxia telangiectasia and rad3-related (ATR) kinase in an inducible fashion were examined for their responses to these two platinating agents and a variety of other DNA cross-linking drugs. The expression of the kdATR allele markedly sensitized the cells to cisplatin, but not to oxaliplatin, as assessed by inhibition of colony formation, induction of apoptosis, and cell cycle analysis. Similar differences in survival were noted for melphalan (ATR dependent) and 4-hydroperoxycyclophosphamide (ATR independent). Further experiments showed that ATR function is not necessary for removal of Pt-DNA adducts. The predominant difference between the responses to the two platinum drugs was the presence of a drug-specific ATR-dependent S-phase arrest after cisplatin but not oxaliplatin. These results indicate that involvement of ATR in the response to DNA cross-linking agents is lesion specific. This observation might need to be taken into account in the development and use of ATR or Chk1 inhibitors. [Mol Cancer Ther 2009;8(4):855–63]

The aim of this study was to review the life of Mary E. O'Sullivan and to summarize her important contributions to the study of migraine. Mary E. O'Sullivan underwent extensive training to become a neurologist at a time when only 5% of women in America were physicians. She published five papers on migraine. In a 1936 Journal of the American Medical Association article, she described a patient with ergotamine overuse headache and recommended that daily doses of oral ergotamine should be avoided. Three years later she described migraine as a ‘complex’ syndrome with multiple causes and multiple cures. Mary E. O'Sullivan, an ambitious female headache specialist of the 1930s, was an early advocate of the use of ergotamine to treat migraine, yet she was one of the first to report ergotamine overuse headache. Although her life was short, her research, knowledge and ambition at a time when women had limited opportunities in medicine have left a mark.

Background— Concern regarding risk of late thrombosis after “off-label” treatment with drug-eluting stents has prompted increased use of bare-metal stents (BMS) in current practice. The sequelae of late BMS failures, however, have been poorly characterized. Methods and Results— We performed a retrospective study of 4503 consecutive patients treated with at least 1 BMS and dual antiplatelet therapy between 1994 and 2000. The cumulative incidence of stent thrombosis was 0.5% at 30 days (95% CI, 0.3% to 0.7%), 0.8% at 1 year (95% CI, 0.6% to 1.1%), and 2.0% at 10 years (95% CI, 1.5% to 2.5%). Risk of late (30 days to 1 year) and very late (>1 year) BMS thrombosis was increased among patients considered off label for drug-eluting stent use ( P =0.024). When saphenous vein graft interventions were excluded, however, risk after off-label use was not significantly increased ( P =0.23). Other correlates included vein graft intervention, prior myocardial infarction (MI), peripheral vascular disease, and ulcerated lesion ( P <0.001). Mortality was markedly increased after late and very late BMS thrombosis, particularly during the first 30 days (hazard ratios, 22 [95% CI, 3.1 to 159] and 40 [95% CI, 15 to 107], respectively). The 10-year incidence of clinical restenosis was 18.1% (95% CI, 16.5% to 19.7%), presenting with MI in 2.1% (95% CI, 1.6% to 2.6%). Restenosis presenting with MI was associated with increased mortality compared with no restenosis (hazard ratio, 2.37; P <0.001) and with restenosis with a non-MI presentation (hazard ratio, 2.42; P <0.001). Conclusions— The incidence of BMS thrombosis and of MI caused by restenosis during extended follow-up is significant. Both complications are associated with mortality.

AbstractWaldenström macroglobulinemia (WM) is an incurable lymphoplasmacytic lymphoma with limited options of therapy. Protein kinase Cβ (PKCβ) regulates cell survival and growth in many B-cell malignancies. In this study, we demonstrate up-regulation of PKCβ protein in WM using protein array techniques and immunohistochemistry. Enzastaurin, a PKCβ inhibitor, blocked PKCβ activity and induced a significant decrease of proliferation at 48 hours in WM cell lines (IC50, 2.5-10 μM). Similar effects were demonstrated in primary CD19+ WM cells, without cytotoxicity on peripheral blood mononuclear cells. In addition, enzastaurin overcame tumor cell growth induced by coculture of WM cells with bone marrow stromal cells. Enzastaurin induced dose-dependent apoptosis at 48 hours mediated via induction of caspase-3, caspase-8, caspase-9, and PARP cleavage. Enzastaurin inhibited Akt phosphorylation and Akt kinase activity, as well as downstream p-MARCKS and ribosomal p-S6. Furthermore, enzastaurin demonstrated additive cytotoxicity in combination with bortezomib, and synergistic cytotoxicity in combination with fludarabine. Finally, in an in vivo xenograft model of human WM, significant inhibition of tumor growth was observed in the enzastaurin-treated mice (P = .028). Our studies therefore show that enzastaurin has significant antitumor activity in WM both in vitro and in vivo, providing the framework for clinical trials to improve patient outcome in WM.