The promise of “personalized medicine” guided by an understanding of each individual’s genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant features. We describe operational implementation of prospective genotyping linked to an advanced clinical decision support system to guide individualized healthcare in a large academic health center. This approach to personalized medicine includes patient and healthcare provider engagement, identifying relevant genetic variation for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most scheduled for cardiac catheterization, were genotyped on a multiplexed platform including CYP2C19 variants that modulate response to the widely-used antiplatelet drug clopidogrel. These data are deposited into the Electronic Medical Record and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.
These data indicate that alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.
A deficiency in essential fatty acid metabolism has been reported in plasma from patients with cystic fibrosis (CF). However, its etiology and role in the expression of disease is unknown. The objective of this study was to determine whether alterations in fatty acid metabolism are specific to CF-regulated organs and whether they play a role in the expression of disease. A membrane lipid imbalance was found in ileum, pancreas, and lung from cftr ؊͞؊ mice characterized by an increase in phospholipid-bound arachidonic acid and a decrease in phospholipid-bound docosahexaenoic acid (DHA). This lipid imbalance was observed in organs pathologically affected by CF including lung, pancreas, and ileum and was not secondary to impaired intestinal absorption or hepatic biosynthesis of DHA. As proof of concept, oral administration of DHA to cftr ؊͞؊ mice corrected this lipid imbalance and reversed the observed pathological manifestations. These results strongly suggest that certain phenotypic manifestations of CF may result from remediable alterations in phospholipid-bound arachidonic acid and DHA levels.docosahexaenoic acid ͉ arachidonic acid ͉ fish oil ͉ pancreas ͉ lung C ystic fibrosis (CF) is the most prevalent lethal autosomal recessive disorder in the Caucasian population, affecting 1 in 2,500 newborns (1). Patients with CF express a typical phenotype characterized by pancreatic insufficiency, ileal hypertrophy, and recurrent pulmonary infections that ultimately lead to pulmonary failure and death. In 1989, the gene whose mutation results in CF was identified and cloned (2, 3). The product of the gene, the CF transmembrane conductance regulator (CFTR), was characterized as an ATP-gated chloride channel that is regulated by cAMP-dependent protein kinase phosphorylation (4).Despite the significant advances made in CF research in recent years, the mechanism by which a mutation in the CFTR gene leads to the manifestations of this disease remains unclear. Although a decrease in apical membrane CFTR-dependent chloride conductance might explain some of the pathological manifestations observed in CF, e.g., viscous secretions, it explains neither the increased inflammation in the lung nor the membrane-recycling defects observed in CF (5-7).Arachidonic acid (AA), an agonist of inflammatory pathways and a stimulant of mucus secretion, is elevated in the phospholipid fraction from bronchial alveolar lavage fluid in CF patients (5). However, the increased inflammation and elevated AA levels observed in CF have long been thought to be secondary to infection (8). This conclusion has been challenged recently by Heeckeren et al. (9), who demonstrated that instillation of agarose beads coated with Pseudomonas into the lungs of cftr Ϫ͞Ϫ mice resulted in increased inflammation and mortality compared with that observed in wild-type mice. These findings suggest that the lungs of cftr Ϫ͞Ϫ mice are primed for inflammation and that the increase in AA and inflammation observed in cftr Ϫ͞Ϫ mice may be a primary event and not secondary to infect...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.