Management of Patients with Ischemic Heart Disease in Spine Surgery.

In ischemic heart disease (IHD), the myocardium does not receive enough blood and oxygen. Although the IHD-related mortality rate is decreasing, the risk remains and is a major predictor of cardiac complications following noncardiac surgery. Given the increase in the older population, the number of patients with spinal diseases requiring surgery is increasing. Among these patients, those with underlying IHD or a high risk of cardiac complications before and after surgery are also increasing. Given that cardiac complications following spinal surgery are associated with delayed patient recovery and even death, spinal surgeons should be knowledgeable about overall patient management, including medication therapy in those at high risk of developing perioperative cardiac complications for successful patient care. Before surgery, the underlying medical conditions of patients should be evaluated. Patients with a history of myocardial infarction should be checked for a history of surgical treatments, and the anticoagulant dose should be controlled depending on the surgery type. In addition, the functional status of patients must be examined before surgery. Functional status can be assessed according to the metabolic equivalent of task (MET). More preoperative cardiac examinations are needed for patients who are unable to perform four METs in daily because of the high risk of postoperative cardiac complications. Patients with a history of IHD require appropriate preoperative management and further postoperative evaluation. When considering surgery, spinal surgeons should be knowledgeable about patient care before and after surgery.

The increased cellular uptake and biliary excretion of curcumin by quercetin: a possible role of albumin binding interaction.

Curcumin and quercetin are natural compounds with a wide spectrum of activities, including antioxidant and anticancer activities. In this study, the combined effect of the two compounds was investigated, with special emphasis on the pharmacokinetics of curcumin by the quercetin-induced changes in the albumin binding of curcumin. We evaluated the effect of quercetin on the binding of curcumin to albumin and on the uptake of curcumin into the cells of the human colon carcinoma cell line WiDr. In addition, we also investigated changes in the in vivo pharmacokinetics of curcumin and curcumin sulfate (the major metabolite of curcumin) coadministered with quercetin. We found that quercetin inhibited the binding of curcumin to albumin and increased the uptake of curcumin into WiDr cells, the human colon carcinoma cell. The quercetin-induced increased uptake (1.6-fold) of curcumin into WiDr cells was also confirmed by an ex vivo study. The in vivo pharmacokinetics of curcumin showed obvious changes when it was coadministered with quercetin, with the significantly lower plasma concentration and greater biliary excretion of curcumin and curcumin sulfate. The present study suggests that quercetin could enhance the cellular uptake of curcumin and modulate in vivo pharmacokinetics of curcumin, and it could be related to albumin-binding interaction.

Genome-wide association study for vascular aging highlights pathways shared with cardiovascular traits in Koreans.

Vascular aging plays a pivotal role in the morbidity and mortality of older people. Reactive hyperemia index (RHI) detected by pulse amplitude tonometry (PAT) is a non-invasive measure of vascular endothelial function and aging-induced pathogenesis of both microvascular and macrovascular diseases. We conducted a genome-wide association study (GWAS) to comprehensively identify germline genetic variants associated with vascular aging in a Korean population, which revealed 60 suggestive genes underlying angiogenesis, inflammatory response in blood vessels, and cardiovascular diseases. Subsequently, we show that putative protective alleles were significantly enriched in an independent population with decelerated vascular aging phenotypes. Finally, we show the differential mRNA expression levels of putative causal genes in aging human primary endothelial cells via quantitative real-time polymerase chain reaction (PCR). These results highlight the potential contribution of genetic variants in the etiology of vascular aging and may suggest the link between vascular aging and cardiovascular traits.

An aptamer-antibody complex (oligobody) as a novel delivery platform for targeted cancer therapies.

Aptamers have recently emerged as reliable and promising targeting agents in the field of biology. However, their therapeutic potential has yet to be completely assessed due to their poor pharmacokinetics for systemic administration. Here, we describe a novel aptamer-antibody complex, designated an "oligobody" (oligomer+antibody) that may overcome the therapeutic limitations of aptamers. To provide proof-of-principle study, we investigated the druggability of oligobody in vivo using cotinine conjugated t44-OMe aptamer, which is specific for the sequence of pegaptanib, and an anti-cotinine antibody. The antibody part of oligobody resulted in extended in vivo pharmacokinetics of the aptamer without influencing its binding affinity. Moreover, the aptamer of oligobody penetrated deeply into the tumor tissues whereas the anti-VEGF antibody did not. Finally, the systemic administration of this oligobody reduced the tumor burden in a xenograft mouse model. Together, these results suggested that our oligobody strategy may represent a novel platform for rapid, low-cost and high-throughput cancer therapy.

Dramatic increase in hepatic and biliary curcumin exposure by modulation of its elimination pathway in rats.

OBJECTIVES: Curcumin, a major component of the food spice turmeric (Curcuma longa), has multiple beneficial effects on diseases of the liver and bile duct. We have investigated whether modulation of the curcumin elimination pathway could increase its hepatic and biliary exposure in rats. METHODS: Probenecid, an inhibitor of the metabolism and biliary excretion of curcumin, was used as a modulator. After intravenous administration of curcumin at a dose of 18 mg/kg/h without (control) or with co-infusion of probenecid (230 mg/kg/h) in rats, the pharmacokinetic parameters of curcumin were estimated. KEY FINDINGS: Coadministration of probenecid significantly increased the total area under the plasma (1.88-fold) and bile (6.73-fold) concentration-time curves from 0 to 80 min of curcumin relative to those in the controls. The tissue-to-plasma concentration ratio in the liver was also dramatically increased (69.3-fold) by probenecid. These results may be attributed to the dual inhibitory effects of probenecid, to a greater extent, on metabolism via glucuronidation, and to a lesser extent, on the biliary excretion of curcumin via the multidrug resistance-associated protein 2. CONCLUSIONS: The probenecid-mediated increase in hepatic and biliary exposure of curcumin suggested that the use of combination drug regimens involving curcumin and modulators of elimination may be an innovative approach for the therapeutic use of curcumin.

p38 kinase-dependent and -independent Inhibition of protein kinase C zeta and -alpha regulates nitric oxide-induced apoptosis and dedifferentiation of articular chondrocytes.

In articular chondrocytes, nitric oxide (NO) production triggers dedifferentiation and apoptotic cell death that is regulated by the converse functions of two mitogen-activated protein kinase subtypes, extracellular signal-regulated kinase (ERK) and p38 kinase. Since protein kinase C (PKC) transduces signals that influence differentiation, survival, and apoptosis of various cell types, we investigated the roles and underlying molecular mechanisms of action of PKC isoforms in NO-induced dedifferentiation and apoptosis of articular chondrocytes. We report here that among the expressed isoforms, activities of PKCalpha and -zeta were reduced during NO-induced dedifferentiation and apoptosis. Inhibition of PKCalpha activity was independent of NO-induced activation of ERK or p38 kinase and occurred due to blockage of expression. On the other hand, PKCzeta activity was inhibited as a result of NO-induced p38 kinase activation and was observed prior to proteolytic cleavage by a caspase-mediated process to generate enzymatically inactive fragments. Inhibition of PKCalpha or -zeta activities potentiated NO-induced apoptosis, whereas ectopic expression of these isoforms significantly reduced the number of apoptotic cells and blocked dedifferentiation. Ectopic expression of PKCalpha or -zeta did not affect p38 kinase or ERK but inhibited the p53 accumulation and caspase-3 activation that are required for NO-induced apoptosis of chondrocytes. Therefore, our results collectively indicate that p38 kinase-independent and -dependent inhibition of PKCalpha and -zeta, respectively, regulates NO-induced apoptosis and dedifferentiation of articular chondrocytes.