Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

A Role for Actin, Cdc1p, and Myo2p in the Inheritance of Late Golgi Elements in \u3cem\u3eSaccharomyces cerevisiae\u3c/em\u3e

In Saccharomyces cerevisiae, Golgi elements are present in the bud very early in the cell cycle. We have analyzed this Golgi inheritance process using fluorescence microscopy and genetics. In rapidly growing cells, late Golgi elements show an actin-dependent concentration at sites of polarized growth. Late Golgi elements are apparently transported into the bud along actin cables and are also retained in the bud by a mechanism that may involve actin. A visual screen for mutants defective in the inheritance of late Golgi elements yielded multiple alleles of CDC1. Mutations in CDC1 severely depolarize the actin cytoskeleton, and these mutations prevent late Golgi elements from being retained in the bud. The efficient localization of late Golgi elements to the bud requires the type V myosin Myo2p, further suggesting that actin plays a role in Golgi inheritance. Surprisingly, early and late Golgi elements are inherited by different pathways, with early Golgi elements localizing to the bud in a Cdc1p- and Myo2p-independent manner. We propose that early Golgi elements arise from ER membranes that are present in the bud. These two pathways of Golgi inheritance in S. cerevisiae resemble Golgi inheritance pathways in vertebrate cells

National trends in utilization, mortality, and survival after repair of type B aortic dissection in the Medicare population

ObjectiveThe application of thoracic endovascular aortic repair (TEVAR) has changed treatment paradigms for thoracic aortic disease. We sought to better define specific treatment patterns and outcomes for type B aortic dissection treated with TEVAR or open surgical repair (OSR).MethodsMedicare patients undergoing type B thoracic aortic dissection repair (2000-2010) were identified by use of a validated International Classification of Diseases, Ninth Revision diagnostic and procedural code–based algorithm. Trends in utilization were analyzed by procedure type (OSR vs TEVAR), and patterns in patient characteristics and outcomes were examined.ResultsTotal thoracic aortic dissection repairs increased by 21% between 2000 and 2010 (2.5 to 3 per 100,000 Medicare patients; P = .001). A concomitant increase in TEVAR was seen during the same interval (0.03 to 0.8 per 100,000; P < .001). By 2010, TEVAR represented 27% of all repairs. TEVAR patients had higher rates of comorbid congestive heart failure (12% vs 9%; P < .001), chronic obstructive pulmonary disease (17% vs 10%; P < .001), diabetes (8% vs 5%; P < .001), and chronic renal failure (8% vs 3%; P < .001) compared with OSR patients. For all repairs, patient comorbidity burden increased over time (mean Charlson comorbidity score of 0.79 in 2000, 1.10 in 2010; P = .04). During this same interval, in-hospital mortality rates declined from 47% to 23% (P < .001), a trend seen in both TEVAR and OSR patients. Whereas in-hospital mortality rates and 3-year survival were similar between patients selected for TEVAR and OSR, there was a trend toward women having slightly lower 3-year survival after TEVAR (60% women vs 63% men; P = .07).ConclusionsSurgical treatment of type B aortic dissection has increased over time, reflecting an increase in the utilization of TEVAR. Overall, type B dissection repairs are currently performed at lower mortality risk in patients with more comorbidities

A Letter of Intent to Install a milli-charged Particle Detector at LHC P5

In this LOI we propose a dedicated experiment that would detect "milli-charged" particles produced by pp collisions at LHC Point 5. The experiment would be installed during LS2 in the vestigial drainage gallery above UXC and would not interfere with CMS operations. With 300 fb$^{-1}$ of integrated luminosity, sensitivity to a particle with charge $\mathcal{O}(10^{-3})~e$ can be achieved for masses of $\mathcal{O}(1)$ GeV, and charge $\mathcal{O}(10^{-2})~e$ for masses of $\mathcal{O}(10)$ GeV, greatly extending the parameter space explored for particles with small charge and masses above 100 MeV.Comment: 19 pages, 7 figure

Thoracic endovascular aneurysm repair, race, and volume in thoracic aneurysm repair

BackgroundVolume-based disparities in surgical care are often associated with poorer results in African American patients. We examined the effect of treatment patterns and outcomes, by race, for isolated thoracic aortic aneurysm (TAA).MethodsUsing Medicare claims (1999-2007), we studied all patients undergoing repair of TAAs, via open surgery or thoracic endovascular aneurysm repair (TEVAR). We studied 30-day mortality and complications by race, procedure type, and hospital volume.ResultsWe studied 12,573 patients who underwent open TAA repair (4% of whom were black) and 2732 patients who underwent TEVAR (8% of whom were black). In open repair, black patients had higher 30-day mortality than white patients (18% vs 10%; P < .001), while mortality rates were similar with TEVAR (8% black vs 9% white; P = .56). For open repair, black patients were more likely to undergo surgery at low-volume hospitals, where overall operative mortality was highest (14% at very low-volume hospitals, 7% at very high-volume hospitals; P < .001). However, for TEVAR, black patients were not more likely to undergo repair at low-volume hospitals, and mortality differences were not evident across volume strata (9% at very low-volume hospitals, 7% at very high-volume hospitals; P = .328). Multivariable analyses adjusting for age, sex, race, comorbidity, and volume confirmed that increased perioperative mortality was associated with black race for open surgery (OR, 2.0, 95% CI, 1.5-2.5; P < .001) but not TEVAR (OR, 0.9, 95% CI, 0.6-1.5; P = .721).ConclusionsWhile racial disparities in surgical care have a significant effect on mortality with open thoracoabdominal aortic aneurysm repair, black patients undergoing TEVAR obtain similar outcomes as white patients. New technology can limit the effect of racial disparities in surgical care

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors reduce the risk of perioperative stroke and mortality after carotid endarterectomy

ObjectiveThere is increasing evidence that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce cardiovascular and cerebrovascular events through anti-inflammatory, plaque stabilization, and neuroprotective effects independent of lipid lowering. This study was designed to investigate whether statin use reduces the incidence of perioperative stroke and mortality among patients undergoing carotid endarterectomy (CEA).MethodsAll patients undergoing CEA from 1994 to 2004 at a large academic medical center were retrospectively reviewed. The independent association of statin use and perioperative morbidity was assessed via multivariate logistic regression analysis.ResultsCEA was performed by 13 surgeons on 1566 patients (987 men and 579 women; mean age, 72 ± 10 years), including 1440 (92%) isolated and 126 (8%) combined CEA/coronary artery bypass grafting procedures. The indication for CEA was symptomatic disease in 660 (42%) cases. Six hundred fifty-seven (42%) patients received a statin medication for at least 1 week before surgery. Statin use was associated with a reduction in perioperative strokes (1.2% vs 4.5%; P < .01), transient ischemic attacks (1.5% vs 3.6%; P < .01), all-cause mortality (0.3% vs 2.1%; P < .01), and median (interquartile range) length of hospitalization (2 days [2-5 days] vs 3 days [2-7 days]; P < .05). Adjusting for all demographics and comorbidities in multivariate analysis, statin use independently reduced the odds of stroke threefold (odds ratio [95% confidence interval], 0.35 [0.15-0.85]; P < .05) and death fivefold (odds ratio [95% confidence interval], 0.20 [0.04-0.99]; P < .05).ConclusionsThese data suggest that perioperative statin use may reduce the incidence of cerebrovascular events and mortality among patients undergoing CEA