Background
In a previous study, the modified Marsh and Schnider models respectively showed negatively‐ and positively‐biased predictions in underweight patients. To overcome this drawback, we ...developed a new pharmacokinetic propofol model‐the Choi model‐for use in underweight patients. In the present study, we evaluated the predictive performance of the Choi model.
Methods
Twenty underweight patients undergoing elective surgery received propofol via TCI using the Choi model. The target effect‐site concentrations (Ces) of propofol were 2.5, 3, 3.5, 4, 4.5, and 2 μg/mL. Arterial blood samples were obtained at least 10 minutes after achieving pseudo‐steady‐state. Predicted propofol concentrations with the modified Marsh, Schnider, and Eleveld pharmacokinetic models were obtained by simulation (Asan pump, version 2.1.3; Bionet Co. Ltd., Seoul, Korea). The predictive performance of each model was assessed by calculation of four parameters: inaccuracy, divergence, bias, and wobble.
Results
A total of 119 plasma samples were used to determine the predictive performance of the Choi model. Our evaluation showed that the pooled median (95% CI) bias and inaccuracy were 4.0 (−4.2 to 12.2) and 23.9 (17.6‐30.3), respectively. The pooled biases and inaccuracies of the modified Marsh, Schnider, and Eleveld models were clinically acceptable. However, the modified Marsh and Eleveld models consistently produced negatively biased predictions in underweight patients. In particular, the Schnider model showed greater inaccuracy at a target Ce ≥ 3 µg/mL.
Conclusion
The new propofol pharmacokinetic model (the Choi model) developed for underweight patient showed adequate performance for clinical use.
Background & Aims Carcinoembryonic antigen (CEA) is expressed by many types of cancer cells; its overexpression induces cell adhesion, increases resistance to anoikis, and promotes hepatic metastasis ...of colon cancer cells. The amino acid sequence PELPK in its hinge region, between the N and A1 domains, is required for migration of cancer cells to the liver. We sought to identify ligands of this domain for use in diagnosis and therapy. Methods We screened for RNA aptamers against the domain of CEA required for metastasis using systematic evolution of ligands by exponential enrichment. The specificity and affinity of the aptamer for CEA protein were characterized by mobility shift, uptake, and surface plasmon resonance assays. We analyzed the effects of the aptamer on metastatic properties of cells, as well as metastasis of colon cancer cells in mice. Results Using systematic evolution of ligands by exponential enrichment, we identified an RNA aptamer that bound to the PELPK sequence in CEA with high affinity and specificity. The isolated aptamer bound specifically to CEA-positive cells and inhibited interactions between CEA and heterogeneous nuclear ribonucleoprotein M4. The aptamer inhibited homotypic aggregation, migration, and invasion by CEA-positive cancer cells, but did not affect adhesion of endothelial cells. The aptamer induced colon cancer cell anoikis by interrupting the interaction between death receptor 5 and CEA. The aptamer prevented metastasis of human colon cancer cells to the livers of mice. Conclusions An RNA aptamer that binds to the PELPK sequence in CEA inhibits its interactions with heterogeneous nuclear ribonucleoprotein M4 and death receptor 5, migration and invasion by colon cancer cells, and hepatic metastasis of colon cancer cells in mice. It promoted cancer cell anoikis and might be used to identify CEA-positive tumors in patients or be developed as an anti-cancer reagent.
Aims
This prospective study aimed to characterize the population pharmacokinetics of intravenous oxycodone and to determine the minimum effective concentration (MEC) and minimum effective analgesic ...concentration (MEAC) of oxycodone for major open intra‐abdominal surgery.
Methods
In the pharmacokinetic study, patients were administered intravenous oxycodone (0.1 mg kg−1), and arterial blood was sampled at pre‐set intervals. In the analgesic‐potency study, patients were administered intravenous oxycodone (0.1 mg kg−1) 30 min before the end of the surgery, were placed in the postoperative anaesthesia care unit (PACU), and were asked to rate their pain every 10 min using a visual analogue scale (0 = no pain, 10 = most severe pain). On the first occasion that wound pain at rest and during compression was rated as ≥3 or ≥5, respectively, the first blood sample was obtained to determine the MEC. A second blood sample was obtained after titration with 2 mg of oxycodone to yield wound pain <3 at rest and <5 during wound compression, and MEAC was determined. MEC and MEAC were determined again in each patient.
Results
In the population pharmacokinetic study (n = 54), oxycodone plasma concentration over time was well described by a three‐compartment mammillary model. Lean body mass and age were significant covariates for the volume of distribution and metabolic clearance of the pharmacokinetic model of oxycodone, respectively. The analgesic‐potency study (n = 50) showed that the median (95% CI) MEC and MEAC were 31.5 (19.2–42.8) and 74.1 (29.2–128.3) ng ml−1 (first measurements) and 63.4 (15.6–120.1) and 76.1 (32.9–132.7) ng ml−1 (second measurements), respectively.
Conclusions
In major intra‐abdominal open surgery, the MEAC and analgesic potency of oxycodone were 75 ng ml−1 and 60 ng ml−1, respectively.
Background Given the increasing use of endoscopic resection as a therapeutic modality for cases of early gastric cancer (EGC), it is very important to define strict criteria for the use of endoscopic ...mucosal resection and endoscopic submucosal dissection. To date, the criteria are almost entirely based on Japanese literature evaluating the risk of lymph node (LN) metastasis in patients with EGC. Objective To analyze our own experience with the factors affecting LN metastasis and to reappraise the extended criteria for endoscopic submucosal dissection. Design Retrospective, single-center study. Setting University teaching hospital. Patients This study involved 478 patients who underwent gastrectomy with LN dissection (n = 270, mucosal m EGC; n = 208, submucosal sm EGC). Intervention Gastrectomy with LN dissection. Main Outcome Measurements LN metastasis. Results Overall, 12.6% (60/478) of patients with EGCs presented with LN metastasis (mEGC, 3.0% 8/270, smEGC, 25.0% 52/208). Increased size, macroscopic type (elevated), depth of invasion, and lymphovascular invasion were associated with LN metastasis. In 270 cases of mEGC, there was no relationship between clinicopathologic features and LN metastasis. In the smEGC group, size, depth of invasion, and lymphovascular emboli were associated with an increased risk of LN metastasis. Significantly, LN metastasis was noted in EGCs falling within established extended endoscopic submucosal dissection criteria, that is, intestinal-type mucosal cancer of any size without ulcer and no lymphovascular emboli (2/146 1.4%) or ≤3 cm with no lymphovascular emboli and irrespective of the presence of ulceration (2/126 1.6%) or intestinal-type submucosal cancer (sm1, <500 μm) without lymphovascular invasion and measuring ≤3 cm in size (3/20 15.0%). Limitations Retrospective review of a single-center study. Conclusion We recommend that more centers survey their experiences of LN metastasis in cases of EGC to refine the criteria for endoscopic submucosal dissection as a therapeutic modality of intestinal-type EGC.
Hepatitis C virus (HCV) is the major cause of progressive liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Previously, we reported that a 29 nucleotide-long 2’-F ...pyrimidine modified RNA aptamer against the HCV nonstructural protein 5B efficiently inhibited HCV replication and suppressed HCV infectious virus particle formation in a cell culture system. In this study, we modified this aptamer through conjugation of cholesterol for in vivo availability. This cholesterol-conjugated aptamer (chol-aptamer) efficiently entered the cell and inhibited HCV RNA replication, without any alteration in gene expression profiling including innate immune response-related genes. Moreover, systemic administration of the chol-aptamer was well tolerated without any abnormalities in mice. To evaluate the pharmacokinetics of the chol-aptamer in vivo, dose proportionality, bioavailability, and pharmacokinetic parameters were evaluated by noncompartmental analyses in normal BALB/c mice. Population analysis was performed using nonlinear mixed effects modeling. Moreover, the pharmacokinetics of two different routes (intravenous, IV, versus intraperitoneal, IP) were compared. Cholesterol conjugation showed dose proportionality, extended the time that the aptamer was in the plasma, and enhanced aptamer exposure to the body. Noticeably, the IV route was more suitable than the IP route due to the chol-aptamer remaining in the plasma for a longer period of time.
Land use and land cover (LULC) form a baseline thematic map for monitoring, resource management, and planning activities and facilitate the development of strategies to balance conservation, ...conflicting uses, and development pressures. In this study, changes in LULC in North Sumatra, Indonesia, are simulated and predicted using an artificial-neural-network-based cellular automaton (ANN-CA) model. Five criteria (altitude, slope, aspect, distance from the road, and soil type) are used as exploratory data in the learning process of the ANN-CA model to determine their impacts on LULC changes between 1990 and 2000; among the criteria, altitude and distance from the road have strong impacts. Comparison between the predicted and the real LULC maps for 2010 illustrates high agreement, with a Kappa index of 0.83 and a percentage of correctness of 87.28%. Then, the ANN-CA model is applied to predict LULC changes in 2050 and 2070. The LULC predictions for 2050 and 2070 demonstrate high increases in plantation area of more than 4%. Meanwhile, forest and crop area are projected to decrease by approximately 1.2% and 1.6%, respectively, by 2050. By 2070, forest and crop areas will decrease by 1.2% and 1.7%, respectively, indicating human influences on LULC changes from forest and cropland to plantations. This study illustrates that the simulation of LULC changes using the ANN-CA model can produce reliable predictions for future LULC.
We investigated the molecular effect and signal pathway of icariin, a major flavonoid of
Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated
in vitro endothelial cell proliferation, ...migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased
in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy.
Abstract Circulating osteoclast precursor cells highly express CX3C chemokine receptor 1 (CX3CR1), which is the only receptor for the unique CX3C membrane-anchored chemokine, fractalkine (CX3CL1). An ...irradiated murine model was used to evaluate the role of the CX3CL1–CX3CR1 axis in osteoclast recruitment and osteoclastogenesis. Ionizing radiation (IR) promoted the migration of circulating CD11b + cells to irradiated bones and dose-dependently increased the number of differentiated osteoclasts in irradiated bones. Notably, CX3CL1 was dramatically upregulated in the vascular endothelium after IR. IR-induced production of CX3CL1 by skeletal vascular endothelium promoted chemoattraction of circulating CX3CR1 +/CD11b + cells and triggered homing of these osteoclast precursor cells toward the bone remodeling surface, a specific site for osteoclast differentiation. CX3CL1 also increased the endothelium-derived expression of other chemokines including stromal cell-derived factor-1 (CXCL12) and macrophage inflammatory protein-2 (CXCL2) by activating the hypoxia-inducible factor-1 α pathway. These effects may further enhance osteoclastogenesis. A series of in vivo experiments confirmed that knockout of CX3CR1 in bone marrow-derived cells and functional inhibition of CX3CL1 using a specific neutralizing antibody significantly ameliorated osteoclastogenesis and prevented bone loss after IR. These results demonstrate that the de novo CX3CL1–CX3CR1 axis plays a pivotal role in osteoclast recruitment and subsequent bone resorption, and verify its therapeutic potential as a new target for anti-resorptive treatment.
The assessments of flood‐prone areas and flood risk due to pluvial flooding for Davao Oriental on Mindanao Island in the Philippines were carried out by the analytic hierarchy process (AHP) and ...maximum entropy (Maxent) models using multiple criteria such as slope, elevation, soil type, rainfall, drainage density, distance to the main channel, and population density. Flood records from 70 survey points were obtained and used to verify the model results. The criteria weights of the top three important factors in the AHP are rainfall (42%), slope (23%), and elevation (15%), whereas those in the Maxent model are elevation (36%), rainfall (23%), and soil (19%). The verification results show that the accuracies of the AHP and Maxent model are 81 and 95.6%, respectively, indicating that both approaches are reliable in flood hazard and risk assessments. Approximately 22% of the total area and approximately 30% of the total population of Davao Oriental are classified as high risk of pluvial flooding in the current situation by the AHP method. This study shows a broad‐scale high‐level data‐driven screening method that can be used to help identify potential hot spots for pluvial flooding for which more detailed numerical modelling studies should be undertaken.
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