Faculty Bibliography

CONTEXT/BACKGROUND:ACTH stimulates adrenocortical steroid production through the melanocortin 2 receptor (MC2R). MC2R trafficking and signaling are dependent on the MC2R accessory protein (MRAP). The MRAP homolog MRAP2 also transports the MC2R to the cell surface but might prevent activation. OBJECTIVE:The objective of the investigation was to study the regulatory pathways of MRAP and MRAP2 and their contributions to ACTH responsiveness in human adrenal tissues. DESIGN AND SETTING/METHODS:MRAP, MRAP2, and MC2R expression levels were studied in 32 human adrenocortical samples. Regulation of these mRNAs was investigated in 43 primary adrenal cultures, stimulated with ACTH, forskolin, angiotensin II (AngII), phorbol-12-myristate-13-acetate (PMA), or dexamethasone. The induction of cortisol, cAMP, and ACTH-responsive genes after treatment with ACTH was related to MRAP, MRAP2, and MC2R expression levels. RESULTS:MRAP and MRAP2 levels were lower in adrenocortical carcinomas (ACC) than in other adrenal tissues (P < 0.001). Patient ACTH and cortisol levels were associated with adrenal levels of MRAP and MC2R in adrenal hyperplasia samples (P < 0.05) but not in tumors. ACTH induced the expression of MRAP 11 ± 2.1-fold and MC2R 20 ± 3.8-fold in all adrenal tissue types (mean ± SEM, both P < 0.0001), whereas AngII augmented these mRNAs 4.0 ± 1.2-fold and 12.6 ± 3.2-fold (P < 0.0001) in all but the ACC. MRAP2 expression was suppressed by forskolin (-24 ± 15%, P = 0.013) and PMA (-22 ± 7%, P = 0.0007). MRAP, MRAP2, or MC2R levels were not associated with the induction of cortisol, cAMP, or gene expression by ACTH in vitro. CONCLUSION/CONCLUSIONS:MRAP and MC2R expression is induced by ACTH and AngII, which would facilitate cell surface receptor availability. Physiological expression levels of MRAP, MRAP2, and MC2R were not limiting for ACTH sensitivity.

(Damage from attacks had long been detected in autopsies.) In time, doctors learned the myriad symptoms that can accompany a heart attack -- among them

Altman revisits the 1982 AIDS Epidemic. Thirty years after scientists gave a frightening new disease its name, AIDS still afflicts millions of men and women around the world. AIDS has infected more than 60 million people worldwide and has killed at least half that number in one of the worst epidemics in history

Consider President Dwight D. Eisenhower's care in 1955, when at 64 he experienced chest pains at 2:30 a.m. while on vacation at his mother-in-law's home in Denver. The White House physician, Dr. Howard M. Snyder, a surgeon, ordered the president's wife, Mamie, to snuggle with her husband in bed to keep him warm. Not until the next afternoon did Snyder perform an electrocardiogram or call for an ambulance. A specialist in internal medicine told him to rest, exercise and stop smoking. [Dick Cheney] had smoked for nearly 20 years, often three or more packs a day. When he was President Gerald R. Ford's chief of staff in the mid-1970s, he helped himself to the cartons of cigarettes in the White House provided free by tobacco companies. Cheney's doctor had a limited arsenal of drugs; for example, statins had yet to be widely prescribed for high cholesterol, and clot-busting drugs were not routinely used. Cheney, who said he took the doctor's advice, resumed campaigning and won election to Congress, mindful that leaders like Eisenhower and President Lyndon B. Johnson had served productively in office despite serious heart attacks

OBJECTIVES/OBJECTIVE:The aim of this study was to investigate the impact of bisphosphonates on the progression of aortic stenosis. BACKGROUND:Valvular calcification is associated with the development and progression of aortic stenosis. Bisphosphonates have been suggested to slow this progression. METHODS:Female patients older than the age of 60 years with an aortic valve area (AVA) between 1.0 and 2.0 cm(2) were identified and studied retrospectively. Only those who had follow-up echocardiograms at least a year apart were included. Primary outcomes were the change in AVA and valvular gradients over time. Mortality and freedom from aortic valve replacement were also studied. A propensity-matching method was applied for the probability of the use of bisphosphonates. RESULTS:The study included 801 female patients (mean age, 76 ± 7.6 years) with a mean follow-up of 5.1 ± 2.4 years. The mean duration of bisphosphonate use was 3.1 ± 2.6 years. At the time of the initial echocardiogram, 323 patients (38%) were taking bisphosphonates. The mean ejection fraction at baseline was 56.7 ± 9.6% with a mean AVA of 1.32 ± 0.25 cm(2). Peak and mean gradients were 28.4 ± 11 mm Hg and 15.6 ± 6.8 mm Hg, respectively. Propensity matching was successfully performed for 438 patients. On follow-up, there were no differences in the rate of change in AVA or peak and mean gradients when patients were stratified based on the use of bisphosphonates. Bisphosphonates also had no impact on survival or freedom from aortic valve replacement. CONCLUSIONS:In this retrospective analysis of older female patients, bisphosphonates do not have a significant impact on the hemodynamic or clinical progression of aortic stenosis.

[...] today it was me with the white coat, and her with the death sentence. A senior resident rescued him before he had a cardiac arrest, then screamed her lungs out at me in front of the entire emergency room staff.

Previous studies have suggested that percutaneous coronary intervention (PCI) decreases long-term mortality in patients with silent myocardial ischemia (SMI), but whether PCI specifically decreases mortality when added to intensive medical therapy is unknown. We performed a post hoc analysis of clinical outcomes in patients in the COURAGE trial based on the presence or absence of anginal symptoms at baseline. Asymptomatic patients were classified as having SMI by electrocardiographic ischemia at rest or reversible stress perfusion imaging (exercise-induced or pharmacologic). Study end points included the composite primary end point (death or myocardial infarction [MI]); individual end points of death, MI, and hospitalization for acute coronary syndrome; and need for revascularization. Of 2,280 patients 12% (n = 283) had SMI and 88% were symptomatic (n = 1,997). There were no between-group differences in age, gender, cardiac risk factors, previous MI or revascularization, extent of angiographic disease, or ischemia by electrocardiogram or imaging. Compared to symptomatic patients, those with SMI had fewer subsequent revascularizations (16% vs 27%, p <0.001) regardless of treatment assignment and fewer hospitalizations for acute coronary syndrome (7% vs 12%, p <0.04). No significant differences in outcomes were observed between the 2 treatment groups, although there was a trend toward fewer deaths in the PCI group (n = 7, 5%) compared to the optimal medical therapy (OMT) group (n = 16, 11%, p = 0.12). In conclusion, addition of PCI to OMT did not decrease nonfatal cardiac events in patients with SMI but showed a trend toward fewer deaths. Although underpowered, given similar outcomes in other small studies, these findings suggest the need for an adequately powered trial of revascularization versus OMT in SMI patients.