The c.-292C>T promoter polymorphism increases reticulocyte-type 15-lipoxygenase-1 activity and could be atheroprotective

Background: Reticulocyte-type 15-lipoxygenase-1 (ALOX15) has anti-inflammatory and inflammatory effects and is implicated in the development of asthma, arthritis and atherosclerosis. Previously, we screened the human ALOX15 gene for variations because genetic variability in ALOX15 might influence these diseases. We found a C>T substitution at position c.-292 in the ALOX15 promoter that created a novel binding site for the transcription factor SPI1 and increased ALOX15 mRNA levels in monocytes from c.-292CT heterozygous volunteers. Methods: To test whether the higher mRNA levels led to higher ALOX15 activity, we performed an activity assay and measured the arachidonic acid metabolite 15(S)-hydroxy-eicosatetraenoic acid [15(S)-HETE] by HPLC analysis. To test whether this polymorphism was associated with coronary artery disease (CAD), we investigated its association in a case-control study involving 498 Caucasians. Results: The c.-292C>T polymorphism was associated with higher enzyme activity in heterozygous carriers. Intriguingly, this polymorphism also showed a tendency to be protective against atherosclerosis. Conclusions: These results suggest that increased ALOX15 activity may attenuate inflammation, which could be caused by an increase in 15(S)-HETE and eventually by its metabolites, the lipoxins. Clin Chem Lab Med 2007;45:487-9

Diagnostic errors in the new millennium: a follow-up autopsy study

A systematic review of the second half of the last century suggested that diagnostic errors have decreased over time. Our previous study covering the years 1972-1992 was then the only time series showing a significant reduction of diagnostic errors from a single institution. We report here the results of a follow-up study a decade later. We analyzed discrepancies between clinical and autoptic diagnoses in 100 randomly selected medical patients who died in the wards and in the medical intensive care unit at a tertiary-care teaching hospital in Switzerland in the year 2002. Autopsy rate declined from around 90% in the years from 1972 to 1992 to 54% in the present study. Major diagnostic errors (class I and II) declined significantly from 30 to 7% (P<0.001) over the last 30 years. Class I errors decreased from 16 to 2% (P<0.001) in the year 2002. Sensitivity for cardiovascular diseases increased from 69 to 92% (P=0.006), for infectious diseases from 25 to 90% (P=0.013) and for neoplastic diseases from 89 to 100% (P=0.053). Specificity for cardiovascular diseases increased from 85 to 98% (P<0.001) but was unchanged at a high level for infectious diseases and neoplastic diseases. The number of diagnostic procedures increased from 144 to 281 (P<0.001) with an increase in the number of computer tomography investigations and of tissue sampling in the last decade. The frequency of major diagnostic errors has been further reduced at the beginning of the new millennium probably due in large part to new diagnostic tools.Modern Pathology advance online publication, 24 February 2012; doi:10.1038/modpathol.2011.199

Rate-Dependent AV Delay Optimization in Cardiac Resynchronization Therapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72066/1/j.1540-8159.2005.40054.x.pd

Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging

This study sought to compare the effects of aggressive and conventional lipid lowering by two different dosages of the same statin on early human atherosclerotic lesions using serial noninvasive magnetic resonance imaging (MRI). Regression of atherosclerotic lesions by lipid-lowering therapy has been reported. Using a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden. Both statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p < 0.001). Total cholesterol decreased by 26% versus 33% and LDL-C by 36% versus 46% in the conventional (20 mg) versus aggressive (80 mg) simvastatin groups, respectively. Although the simvastatin 80-mg group had significantly higher baseline TC and LDL-C levels, both groups reached similar absolute values after treatment. A significant reduction in VWA was already observed by 12 months. No difference on vascular effects was detected between the randomized doses. Post-hoc analysis showed that patients reaching mean on-treatment LDL-C < or = 100 mg/dl had larger decreases in plaque size. Effective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin

Effects of aggressive versus conventional lipid-lowering therapy by simvastatin on human atherosclerotic lesions: a prospective, randomized, double-blind trial with high-resolution magnetic resonance imaging

ObjectivesThis study sought to compare the effects of aggressive and conventional lipid lowering by two different dosages of the same statin on early human atherosclerotic lesions using serial noninvasive magnetic resonance imaging (MRI).BackgroundRegression of atherosclerotic lesions by lipid-lowering therapy has been reported.MethodsUsing a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden.ResultsBoth statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p ConclusionsEffective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin.Roberto Corti, Valentin Fuster, Zahi A. Fayad, Stephen G. Worthley, Gerard Helft, William F. Chaplin, Jörg Muntwyler, Juan F. Viles-Gonzalez, Jesse Weinberger, Donald A. Smith, Gabor Mizsei, Juan J. Badimo