The power of Pasteur's quadrant: cardiovascular disease at the turn of the century.

During the life span of The FASEB Journal, the decline in cardiovascular mortality was astonishing as the fundamental bases of the complex syndromes of cardiovascular disease were illuminated. In this Silver Anniversary Review, we highlight a few pivotal advances in the field and relate them to research in Pasteur's quadrant, the region of investigation driven by both a desire for fundamental understanding and the consideration of its use. In the second half of the 20th century, we advanced from little pathophysiologic understanding to a near-complete understanding and effective, evidence-based therapeutics for vascular disorders and a similar development of pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. In the current era, we have witnessed "the rise of the machines," from stents to cardiac resynchronization therapy. The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders. We briefly consider the promise of regenerative medicine and are intrigued by the possibility for the direct reprogramming of resident cardiac fibroblasts into cardiomyocytes. As for the future, genomic profiling should help physicians recommend individualized risk factor modification targeted to prevent specific manifestations of cardiovascular disease. Transcriptional and biomarker analyses will almost surely be used individually to tailor therapy for those at risk of or experiencing cardiovascular disease. Given the ongoing exponential expansion of scientific knowledge, all of human ingenuity will be needed to fully utilize the power of Pasteur's quadrant and to unleash another quarter century in cardiology as scientifically fruitful and effective on human health as the last.

Oxalic acid alters intracellular calcium in endothelial cells.

Patients with chronic renal failure (CRF) who undergo hemodialysis experience accelerated atherosclerosis and premature death. While the cause of uremic atherogenesis is unknown, we reported that uremic levels of oxalate, an excretory metabolite, severely inhibit proliferation and migration of human endothelial cells (EC) without affecting other cell types. Since the physical, cellular and molecular events of endothelial injury are clearly established as key factors in the development of plaque, and since inhibition of proliferation and migration would enhance endothelial injury, we have proposed that oxalate is an atherogenic toxin of uremia. In the current study, we used in situ cell counting and total DNA measurement to show that the inhibitory effect of oxalate on proliferation is exclusive to endothelial cells among human cell lines tested (endothelial cells, fibroblasts, aortic smooth muscle cells (SMC), glioblastoma and embryonic kidney cells). Using the fluorescent calcium indicators fura-2 and fluo-3, we correlated the inhibition of proliferation with a prolonged elevation in intracellular free calcium levels. We also demonstrated that all cells tested internalize 14C-oxalic acid. We conclude that plasma oxalate exerts its atherogenic effects by elevating intracellular calcium exclusively in endothelial cells and preventing re-endothelialization.

Coronary artery disease and opioid use.

Over the past 20 years, we have observed a paucity of morbidity and mortality due to cardiovascular disease among drug users in a methadone maintenance clinic. The present study investigated whether long-term exposure to opiates or opioids is associated with decreased severity of coronary artery disease (CAD) by comparing 98 decedents with methadone or opiates (M/O) in their blood at autopsy with 97 frequency-matched decedents without M/O. Severe CAD was found significantly less often in M/O-positive decedents (5 of 98) than in M/O-negative decedents (16 of 97). Multiple logistic regression analysis contrasting those with moderate or severe CAD to those with no or mild CAD yielded an odds ratio of 0.43 (95% confidence interval 0.20 to 0.94) for M/O positivity after adjustment for potential confounding. Long-term opiate exposure thus may mitigate CAD severity and its often fatal consequences.

Medical humanities at New York University School of Medicine: an array of rich programs in diverse settings.

The New York University School of Medicine has a rich tradition of cultivating programs in medical humanities and professionalism. They are drawn from the departments, centers, students, and faculty in the School of Medicine, have linkages throughout the university, and are interwoven into the fabric and culture of the institution. Some are centrally based in the School of Medicine's deans' office, and others are located in individual departments and receive support from the dean's office. This article describes representative programs for medical students and faculty. Curricular initiatives, the fundamental components of medical students' learning, include a course entitled "The Physician, Patient, and Society," a clerkship essay in the Medicine Clerkship, an opportunity for reflection during the medicine clerkship, and a medical humanities elective. In 2002, the Professionalism Initiative was launched to enhance and reflect the values of the medical profession. Its curriculum consists of a series of events that coordinate, particularly, with existing elements of the first-year curriculum (e.g., orientation week, a session during anatomy, a self-assessment workshop, and a peer-assessment workshop). The Master Scholars Program is a group of five, theme-based master societies consisting of faculty and students who share common interests around the society's themes. Programs developed for the societies include colloquia, faculty-led seminars, a mandatory student-mentoring program, and visiting scholars. Finally, the authors describe three high-quality literary publications created at New York University School of Medicine. Each of the initiatives undergoes regular critical examination and reflection that drive future planning.