Natural History Of Syphilitic Aortitis

No large studies of cardiovascular syphilis at necropsy have been reported since 1964. We examined at necropsy 90 patients who had characteristic morphologic findings of syphilitic aortitis. None had ever undergone cardiovascular surgery. With the exception of 2 cases seen more recently, the hearts and aortas of the 90 patients were examined and categorized by one of us (W.C.R.) from 1966 to 1990. All 90 had extensive involvement of the tubular portion of the ascending aorta by the syphilitic process, which spared the sinuses of Valsalva in all but 4 patients. The aortic arch was also involved in 49 (91%) of 54 patients and the descending thoracic aorta in 47 (90%) of 52 patients. Syphilis was the cause of death in 23 (26%) of the 90 patients. It was secondary to rupture of the ascending or descending thoracic aorta in 12, severe aortic regurgitation leading to heart failure in 10, and severe narrowing of the aortic ostium of the right coronary artery in 1 patient. Of the 40 patients who had undergone serologic testing for syphilis, 28 (70%) had a positive (reactive) finding. Those patients with a negative or nonreactive test or who did not undergo a serologic test for syphilis had morphologic and histologic findings in the aorta at necropsy similar to the findings of those patients who had had a positive serologic test for syphilis. In conclusion, cardiovascular syphilis has not disappeared. In patients with dilated ascending aortas, with or without aortic regurgitation, a serologic test for syphilis is recommended. If the findings are positive or if characteristic morphologic features of cardiovascular syphilis are suspected, irrespective of the results of the serologic tests, antibiotic therapy appears desirable. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:1578-1587)Integrative Biolog

Presence Of A Congenitally Bicuspid Aortic Valve Among Patients Having Combined Mitral And Aortic Valve Replacement

Although bicuspid aortic valve occurs in an estimated 1% of adults and mitral valve prolapse in an estimated 5% of adults, occurrence of the 2 in the same patient is infrequent. During examination of operatively excised aortic and mitral valves because of dysfunction (stenosis and/or regurgitation), we encountered 16 patients who had congenitally bicuspid aortic valves associated with various types of dysfunctioning mitral valves. Eleven of the 16 patients had aortic stenosis (AS): 5 of them also had mitral stenosis, of rheumatic origin in 4 and secondary to mitral annular calcium in 1; the other 6 with aortic stenosis had pure mitral regurgitation (MR) secondary to mitral valve prolapse in 3, to ischemia in 2, and to unclear origin in 1. Of the 5 patients with pure aortic regurgitation, each also had pure mitral regurgitation: in 1 secondary to mitral valve prolapse and in 4 secondary to infective endocarditis. In conclusion, various types of mitral dysfunction severe enough to warrant mitral valve replacement occur in patients with bicuspid aortic valves. A proper search for mitral valve dysfunction in patients with bicuspid aortic valves appears warranted. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:263-271)Integrative Biolog

Effect Of Coronary Bypass And Valve Structure On Outcome In Isolated Valve Replacement For Aortic Stenosis

Reports differ regarding the effect of concomitant coronary artery bypass grafting (CABG) in patients who undergo aortic valve replacement (AVR) for aortic stenosis (AS), and no reports have described the effect of aortic valve structure in patients who undergo AVR for AS. A total of 871 patients aged 24 to 94 years (mean 70) whose AVR for AS was their first cardiac operation, with or without first concomitant CABG, were included. Patients who underwent mitral valve procedures were excluded. In comparison with the 443 patients (51%) who did not undergo CABG, the 428 (49%) who underwent concomitant CABG were significantly older, were more often male, had lower transvalvular peak systolic pressure gradients and larger valve areas, had lower frequencies of congenitally malformed aortic valves, had lighter valves by weight, had higher frequencies of systemic hypertension, and had longer stays in the hospital after AVR. Early and late (to 10 years) mortality were similar by propensity-adjusted analysis in patients who did and did not undergo concomitant CABG. Congenitally unicuspid or bicuspid valves occurred in approximately 90% of those aged 21 to 50, in nearly 70% in those aged 51 to 70 years, and in just over 30% in those aged 71 to 95 years. Unadjusted and adjusted survival was significantly higher in patients with unicuspid or bicuspid valves compared to those with tricuspid valves. In conclusion, although concomitant CABG had no effect on the adjusted probability of survival, the type of aortic valve (unicuspid or bicuspid vs tricuspid) significantly affected the unadjusted and adjusted probability of survival. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109:1334-1340)Statistic

Cwp84, a Clostridium difficile cysteine protease, exhibits conformational flexibility in the absence of its propeptide

In recent decades, the global healthcare problems caused by Clostridium difficile have increased at an alarming rate. A greater understanding of this antibiotic-resistant bacterium, particularly with respect to how it interacts with the host, is required for the development of novel strategies for fighting C. difficile infections. The surface layer (S-layer) of C. difficile is likely to be of significant importance to host–pathogen interactions. The mature S-layer is formed by a proteinaceous array consisting of multiple copies of a high-molecular-weight and a low-molecular-weight S-layer protein. These components result from the cleavage of SlpA by Cwp84, a cysteine protease. The structure of a truncated Cwp84 active-site mutant has recently been reported and the key features have been identified, providing the first structural insights into the role of Cwp84 in the formation of the S-layer. Here, two structures of Cwp84 after propeptide cleavage are presented and the three conformational changes that are observed are discussed. These changes result in a reconfiguration of the active site and exposure of the hydrophobic pocket

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead