The purpose of this study was to compare sympathetic nerve activity responses to the cold pressor test in black and white normotensive subjects. We recorded muscle sympathetic nerve activity (microneurography of the peroneal nerve), arterial blood pressure, and heart rate in 9 normotensive American blacks (24±2 years, mean±SEM) and 10 normotensive American whites (28±2 years) at rest and during hand immersion in ice water (cold pressor test). Body weight was not different in the two groups (72.4±3.7 versus 74.1 ±3.8 kg, black versus white subjects). During supine rest, mean arterial pressure (92±2 versus 93±3 mm Hg, black versus white), heart rate (66±4 versus 62±3 beats per minute, black versus white), and muscle sympathetic nerve burst frequency (12±2 versus 17±3 bursts per minute, black versus white) were not different in the two groups. During the cold pressor test, mean arterial pressure, heart rate, and muscle sympathetic nerve activity increased from supine rest in both groups. The magnitudes of increases in mean arterial pressure and total minute muscle sympathetic nerve activity were significantly greater in blacks than whites (33.5±3 versus 22.4±3 mm Hg and 416±24% versus 243±31% of control, respectively, black versus white, P<.05). The increases in heart rate were not significantly different for the two groups. These data suggest that the enhanced pressor response to cold stress observed in normotensive blacks is attributable to greater increases in peripheral sympathetic nerve activity. This heightened sympathetic response to stress may predispose blacks to the development of hypertension. 5 This heightened pressor response to stress may be important in the pathogenesis of hypertension, because it characterizes the early stages of hypertension. "9 The mechanism of the heightened pressor response to stress in blacks remains speculative. The greater stress-induced increase in blood pressure observed in blacks is accompanied by greater increases in peripheral vascular resistance. 4 ' 10 Such increases in peripheral vascular resistance could be mediated by humoral factors or by increases in peripheral sympathetic nervous system reactivity. However, indirect assessments of sympathetic nervous system activity, such as measurements of venous plasma norepinephrine levels, have not suggested significant racial differences in sympathetic nervous system reactivity. 11Microneurographic measurement of efferent sympathetic nerve traffic to skeletal muscle is now commonly used to evaluate peripheral sympathetic nervous system activity in humans.12 Because muscle sympathetic nervous system activity (MSNA) is directly measured from peripheral nerves, microneurography is more sensitive and specific than traditional indirect assessments of sympathetic nervous system activity. 13 With the use of microneurography, small but significant perturbations in sympathetic nervous system activity can be demonstrated that may not be seen with conventional assessments of sympathetic nervous system activity, such as measurement of v...

Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the “benign” senescent cells that surround and support AML.

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The development and implementation of an interdisciplinary oncology program resulted in decreased medication-error rates, expanded pharmacy services, and cost savings.