The Na+-Ca2+ exchanger gene (Ncx1) is upregulated in hypertrophy and is often found elevated in end-stage heart failure. Studies have shown that the change in its expression contributes to contractile dysfunction. β-adrenergic receptor (β-AR) signaling plays an important role in the regulation of calcium homeostasis in the cardiomyocyte but chronic activation in periods of cardiac stress contribute to heart failure by mechanisms which include Ncx1 upregulation. Here, using a Ca2+/Calmodulin-Dependent Protein Kinase II (CaMKIIδc) null mouse, we demonstrate that β-AR-stimulated Ncx1 upregulation is dependent on CaMKII. β-AR-stimulated Ncx1 expression is mediated by activator protein 1 (AP-1) factors and is independent of cAMP-response element-binding protein (CREB) activation. The MAP kinases (ERK1/2, JNK and p38) are not required for AP-1 factor activation. Chromatin immunoprecipitation demonstrates that β-AR stimulation activates the ordered recruitment of JunB homodimers which then are replaced by c-Jun homodimers binding to the proximal AP-1 elements of the endogenous Ncx1 promoter. In conclusion, this work has provided insight into the intracellular signaling pathways and transcription factors regulating Ncx1 gene expression in a chronically β-AR-stimulated heart.

The ethical and scientific literature reflects a certain amount of controversy and confusion surrounding the concept of death by neurological criteria, or brain death. The issues surrounding brain death occur with limited frequency for those working in acute critical care settings. Even so, the literature and our own experiences evidence the discomfort of caregivers and policymakers when dealing with brain-dead patients and their family and loved ones. One particular area in which there seems to be significant diversity of opinion is what should occur when death by neurological criteria is pronounced. At some hospitals, when the patient is pronounced dead by neurological criteria, the support equipment is removed from the body immediately and the body is prepared for visitation by family or is transported to the morgue. In other hospitals, support equipment is maintained for a certain limited period to allow the family to be present when the equipment is ultimately removed. In general, however, it appears that institutional guidelines and policy are vague, at best, or often silent about the issue of when, how, and, to some extent, who decides what is done with the body. This policy paper discusses the confusion of care providers as well as lay persons related to the general concepts of death by neurological criteria. In addition, alternative approaches to the withdrawal of support equipment are examined. This article may also allow nursing administrators to better understand the importance of establishing specific clinical guidelines for their staff related to patients declared dead by neurological criteria. Our conclusion is that a universal policy should be adopted whereby all institutions develop the same guidelines concerning when and how treatment modalities should be withdrawn on their brain-dead patients. Such policy guidelines may not extinguish the misconceptions, misunderstandings, and discomforts that are present with a diagnosis of brain death, but it would certainly allow for more consistent actions on the part of the caregivers. Consistency would substantially benefit caregivers, families, and society alike.