Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (

CD36 modulates platelet function via binding to oxidized LDL (oxLDL), cell-derived microparticles, and thrombospondin-1. We hypothesized that the level of platelet CD36 expression may be associated with inheritance of specific genetic polymorphisms and that this would determine platelet reactivity to oxLDL. Analysis of more than 500 subjects revealed that CD36 expression levels were consistent in individual donors over time but varied widely among donors (

Our previous genomewide linkage scan of 428 nuclear families (GeneQuest) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on chromosome 1p34-36. We analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from the GeneQuest families (381 cases) and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. Three additional white populations were used for follow-up replication studies: another independent cohort of CAD- and/or MI-affected families (GeneQuest II: 441 individuals from 22 pedigrees), an Italian cohort with familial MI (248 cases) and 308 Italian controls, and a separate Cleveland GeneBank cohort with sporadic MI (1,231 cases) and 560 controls. The association was significantly replicated in two independent populations with a family history of CAD and/or MI, the GeneQuest II family-based replication cohort and the Italian cohort, but not in the population with sporadic disease. The R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase by oxidized low-density lipoprotein. This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI.

Aging is associated with both the disturbances of circadian rhythms and a prothrombotic phenotype. It remains poorly understood how the circadian system regulates thrombosis, a critical outcome of aging-related cardiovascular disease. Using multiple in vivo models, we now show that mice with genetic ablation of the core clock gene Bmal1, which display pre-mature aging, have a dramatic prothrombotic phenotype. This phenotype is mechanistically linked to changes in the regulation of key risk factors for cardiovascular disease. These include circulating vWF, fibrinogen, and PAI-1, all of which are significantly elevated in Bmal1 −/− mice. We also show that major circadian transcriptional regulators CLOCK and Bmal1 directly regulate the activity of vWF promoter and that lack of Bmal1 results in upregulation of vWF both at mRNA and protein level. Here we report a direct regulation of vWF expression in endothelial cells by biological clock gene Bmal1. This study establishes a mechanistic connection between Bmal1 and cardiovascular phenotype.The circadian clock system regulates a number of physiological functions in humans and provides a mechanism for the adaptation of an organism to daily changes in the environment (Panda et al., 2002;Lowrey and Takahashi, 2004). It is involved in the progression of a number of human pathological processes, and may determine the success or failure of therapeutic interventions. Numerous clinical studies have demonstrated that acute cardiovascular events (myocardial infarction, stroke, and sudden death) follow diurnal pattern (Muller et al., 1985; Willich, 1990) suggesting the involvement of the components of the circadian clock in their regulation. These include two basic helix-loop-helix (bHLH)-PAS domain-containing transcription factors, CLOCK, and Bmal1, which regulate expression of genes through E-box elements in their promoters and their transcriptional

Lean methodologies have been applied in many industries to reduce waste. We applied Lean techniques to redesign laboratory workstations with the aim of reducing the number of times employees must leave their workstations to complete their tasks. At baseline in 68 workflows (aggregates or sequence of process steps) studied, 251 (38%) of 664 tasks required workers to walk away from their workstations. After analysis and redesign, only 59 (9%) of the 664 tasks required technologists to leave their workstations to complete these tasks. On average, 3.4 travel events were removed for each workstation. Time studies in a single laboratory section demonstrated that workers spend 8 to 70 seconds in travel each time they step away from the workstation. The redesigned workstations will allow employees to spend less time travelling around the laboratory. Additional benefits include employee training in waste identification, improved overall laboratory layout, and identification of other process improvement opportunities in our laboratory.