23 research outputs found
Management of Worsening Heart Failure With Reduced Ejection Fraction:<i>JACC </i>Focus Seminar 3/3
Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.</p
Mechanisms of MEOX1 and MEOX2 Regulation of the Cyclin Dependent Kinase Inhibitors p21CIP1/WAF1 and p16INK4a in Vascular Endothelial Cells
Senescence, the state of permanent cell cycle arrest, has been associated
with endothelial cell dysfunction and atherosclerosis. The cyclin dependent
kinase inhibitors p21CIP1/WAF1 and p16INK4a govern the
G1/S cell cycle checkpoint and are essential for determining whether
a cell enters into an arrested state. The homeodomain transcription factor
MEOX2 is an important regulator of vascular cell proliferation and is a direct
transcriptional activator of both p21CIP1/WAF1 and p16INK4a.
MEOX1 and MEOX2 have been shown to be partially functionally redundant during
development, suggesting that they regulate similar target genes in
vivo. We compared the ability of MEOX1 and MEOX2 to activate p21CIP1/WAF1
and p16INK4a expression and induce endothelial cell cycle arrest.
Our results demonstrate for the first time that MEOX1 regulates the MEOX2
target genes p21CIP1/WAF1 and p16INK4a. In addition,
increased expression of either of the MEOX homeodomain transcription factors
leads to cell cycle arrest and endothelial cell senescence. Furthermore, we
show that the mechanism of transcriptional activation of these cyclin dependent
kinase inhibitor genes by MEOX1 and MEOX2 is distinct. MEOX1 and MEOX2 activate
p16INK4a in a DNA binding dependent manner, whereas they induce
p21CIP1/WAF1 in a DNA binding independent manner
Multiple carriers for dipeptide transport: carrier-mediated transport of glycyl-L-proline in renal BBMV
Identification and characterization of a monoclonal antibody recognizing a galactose-binding domain of the toxin ricin
A monoclonal antibody raised against purified ricin B chain, 75/3B12, blocked ricin toxicity 30- to 100-fold in vitro. The 75/3B12 IgG and F(ab');2 blocked ricin binding to cell surface galactose-containing receptors. The 75/3B12 Fab bound ricin D with a Ka of 10(7) M-1, and this binding was blocked by asialofetuin, lactose, and N-acetylgalactosamine--molecules which interact with the ricin galactose-binding site--but not by fetuin, sucrose, or glucose. The 75/3B12 Fab contained no detectable carbohydrate and, according to several lines of evidence, did not bind ricin via Ig carbohydrate determinants. The monoclonal antibody appears to recognize a galactose-binding site on ricin D via the variable region of the antibody. The 75/3B12 Fab bound ricin E only 1/50 as well as ricin D and bound the Ricinus agglutinin only 1/80 as well as ricin D. The antibody specificity indicates that structural differences exist in the galactose-binding sites of the Ricinus communis lectins. Abrin and other lectins which bind galactose or N-acetylgalactosamine were not significantly bound by the monoclonal antibody. In vitro, the antibody blocked the nontarget toxicity of immunotoxins similarly to lactose. However, in vivo, unlike lactose, the 75/3B12 antibody protected mice from ricin toxicity
704-1 Relationship Between Regional Myocardial Blood Flow and Regional Wall Motion at Rest and with Stress in Humans with Chronic Ischemic Heart Disease
Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions
Management of Worsening Heart Failure With Reduced Ejection Fraction:JACC Focus Seminar 3/3
Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient.</p