Cheng-Deng Kuo

Heart rate variability measures as predictors of in-hospital mortality in ED patients with sepsis

OBJECTIVE To determine the predictive capability of heart rate variability (HRV) measures of patients with sepsis in the ED for in-hospital death. METHODS This was a prospective, observational study. A consecutive cohort of patients visiting the ED of a university teaching hospital who met the criteria of sepsis over a 6-month period were enrolled in this study. General demographics, vital signs, laboratory data, and Mortality in Emergency Department Sepsis score were obtained in the ED; the in-patient medical record was reviewed; and a series of continuous 10-minute electrocardiographic signals were recorded for off-line HRV analysis to assess the in-hospital mortality of the patients. RESULTS One hundred thirty-two patients aged 27 to 86 years who met the inclusion criteria were enrolled. According to the in-hospital outcome, the patients were categorized into 2 groups: nonsurvivors (n = 10) and survivors (n = 122). The baseline HRV measures, including SDNN, TP, VLFP, LFP, and LFP/HFP ratio, of nonsurvivors were significantly lower, whereas the nHFP was significantly higher, than those of survivors. Multiple logistic regression model identified SDNN and nHFP as the significant independent variables in the prediction of in-hospital mortality for ED patients with sepsis. The receiver operating characteristic area for SDNN and nHFP in predicting the risk of death was 0.700 and 0.739, respectively. CONCLUSIONS Heart rate variability measures, especially the SDNN and nHFP, may be used as valuable predictors of in-hospital mortality in patients with sepsis attending the ED.

Norcantharidin induces anoikis through Jun-n-terminal kinase activation in Ct26 colorectal cancer cells

Norcantharidin (NCTD), a chemically modified form of cantharidin, is a potential anticancer drug. This study investigated the effect of NCTD on anoikis in CT26 colorectal adenocarcinoma cells. NCTD treatment of CT26 cells showed a dose-dependent and time-dependent decrease in viability and cell proliferation. Growth inhibition was accompanied by cell cycle arrest in the S and G2/M phases. Mitogen-activated protein kinase expression, assayed by Western blot, was unchanged except for Jun-N-terminal kinase (JNK). At 24 h of treatment with 0–20 μmol/l NCTD, JNK expression increased at 24 h, but then decreased at 48 h; in contrast, the phosphorylated JNK levels markedly increased. JNK inhibitor (SP600125) in the culture effectively blocked NCTD-induced cytotoxicity and detachment of cells. CT26 cells treated with NCTD not only displayed inhibited cell adhesion and down-expression of integrin &bgr;1, but also changed from being shuttle-shaped to round, the latter cells being more susceptible to anoikis-mediated apoptosis. Flow cytometric assay of the DNA content in NCTD-treated CT26 cells at 24 and 48 h showed a marked increase in the sub-G1 level, indicating that NCTD induced apoptosis. NCTD inhibited the viability of CT26 cancer cells preferentially over normal bone marrow and mononuclear cells. NCTD inhibits CT26 cancer cells by blocking proliferation and inducing anoikis-mediated apoptosis, a process that might be regulated by JNK activation.

A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells.

Norcantharidin (NCTD) is a small-molecule metastasis inhibitor without renal toxicity derived from a renal toxic compound cantharidin, which is found in blister beetles (Mylabris phalerata Pall.), commonly used in traditional Chinese medicine. The anti-metastatic capacity of NCTD is apparently through the downexpression of matrix metalloproteinase-9 (MMP-9) activity. The aim of this study was to clarify the transcriptional regulation of MMP-9 gene by NCTD in colorectal cancer CT-26 cells. NCTD not only downregulated MMP-9 mRNA and protein expression, but also inhibited gelatinase activity in a concentration- and time-dependent manner. In CT26 cells with transfection of cis-element reporter plasmids, NCTD treatment decreased reporter luciferase activity from a Sp1 construct, augmented with a NF-kappaB construct, but this did not occur with an AP-1 construct. Further transfecting with constructs containing wild-type or various mutant MMP-9 promoters in CT26 cells indicated that Sp1, but not the others, was required for NCTD-inhibition of MMP-9 promoter transactivation. More evidence by electrophoretic mobility shift assay demonstrated that NCTD inhibited the DNA-binding activity of Sp1. In addition, the increase effect of NF-kappaB-luciferase activity by NCTD may include the upexpression of nuclear STAT1 and result in competitive suppression of NF-kappaB-binding activity in MMP-9 promoter. In conclusion, the metastasis inhibitor NCTD downregulates MMP-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer CT26 cells.

Perioperative plasma concentrations of tumor necrosis factor-alpha and interleukin-6 in infected patients.

OBJECTIVE To characterize the sequential plasma concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and their relationship with the clinical outcome in patients with intra-abdominal infection who underwent surgical intervention. DESIGN A prospective, comparative study. SETTING Surgical intensive care unit of a university hospital. PATIENTS Fifteen patients with surgically proved intra-abdominal infection were included as the infected group. The comparative noninfected group consisted of ten patients who underwent major abdominal surgery without infection. INTERVENTIONS Blood samples were obtained from the indwelling arterial catheter before induction of general anesthesia, and 1, 1.5, 2, 3, 4, 6, and 24 hrs after skin incision. MEASUREMENTS AND MAIN RESULTS Plasma cytokine concentrations were measured using radioimmunoassay. The hemodynamic and physiologic parameters were recorded for comparison with cytokine concentrations. In the noninfected group, the TNF-alpha concentration was very low throughout the observation period, and the IL-6 concentration increased 4 hrs after skin incision. The infected group had significantly higher TNF-alpha and IL-6 concentrations than the noninfected group. The TNF-alpha concentration increased from 129.2 +/- 46.4 to 1196.0 +/- 445.8 pg/mL and the IL-6 concentration increased from 54.2 +/- 24.3 to 560.3 +/- 187.5 pg/mL 2 hrs after skin incision in the infected group. The postoperative APACHE II score correlated significantly with both peak IL-6 (r2=.39) and peak TNF-alpha (r2=.32) concentrations. CONCLUSIONS Both TNF-alpha and IL-6 concentrations increased significantly after surgical intervention in patients with intra-abdominal infection. The pulse increase in TNF-alpha concentration and the persistent increase in IL-6 concentration were related to the poor postoperative clinical condition in infected patients.

Inhibitory effect of norcantharidin, a derivative compound from blister beetles, on tumor invasion and metastasis in CT26 colorectal adenocarcinoma cells

Norcantharidin (NCTD), a potential anti-cancer drug, is the demethylated analog of cantharidin isolated from blister beetles. The present study investigated the effect of NCTD on tumor invasion and metastasis. A cytotoxicity assay of NCTD in CT26 colorectal adenocarcinoma cells showed a dose- and time-dependent decrease in cell viability. NCTD (50 μM)-treated CT26 cells not only showed an inhibited cell invasion of 65.6%, but also decreased the activity of matrix metalloproteinase-2 and -9. NCTD decreased the adhesive ability of CT26 cells in a dose-dependent manner. At a concentration of 100 μM, NCTD showed a down-expression of several cadherin–catenin adhesion molecules, including Desmoglein, N-cadherin, and &agr;- and &bgr;-catenin, while there were no obvious changes in E-cadherin and &ggr;-catenin. Intraperitoneal injection of NCTD (2 mg/kg/day) in BALB/c mice reduced both the pulmonary metastatic capacity of CT26 cells and prolonged the survival day of the mice. These results demonstrated that it was effective in blocking both tumor invasion and metastasis.

Sequential changes in heart rate variability after coronary artery bypass grafting

Heart rate variability (HRV) decreased soon after coronary artery bypass grafting and returned to the preoperative level within 2 months; however, HRV did not exceed the preoperative level, even 6 months after coronary artery bypass grafting. Although myocardial ischemia can be improved by coronary artery bypass grafting, HRV did not benefit from coronary artery bypass grafting within 6 months.

Norcantharidin is a small-molecule synthetic compound with anti-angiogenesis effect.

AIMS This study examined the in vitro and in vivo angiogenic effects of norcantharidin (NCTD), a synthetic, small-molecule antitumor compound. MAIN METHODS Syngeneic colorectal adenocarcinoma CT26 cells were implanted in mice to examine the effect of NCTD on VEGF production and renal and hepatic toxicity. Human umbilical endothelial cells (HUVECs) were used to examine the in vitro effect of NCTD on viability, chemotaxis, vascular network tube formation, adhesive ability, anoikis, and mitogen-activated protein kinase (MAPK) signaling. A protein array was used for analysis of angiogenic factors released from NCTD-treated HUVECs. KEY FINDINGS NCTD suppressed plasma VEGF levels of tumor-bearing mice, without renal or hepatic toxicity. In vitro, NCTD inhibited viability of normal HUVECs to a lesser extent than CT26 cancer cells. At concentrations less than those inhibiting 50% of the cells, NCTD inhibited migration and capillary-like tube formation of HUVECs. The anti-angiogenic effect of NCTD was accompanied by anoikis, down-regulation of integrin beta1, and breakdown of vimentin. NCTD decreased MAPK expression of phosphorylated (p)-JNK and p-ERK. P-P38 expression or P38 inhibitor SB203580 did not impair the effect of NCTD on viability or adhesion of HUVECs. In addition, NCTD inhibited the release of pro-angiogenic factors from HUVECs, but not from CT26 cells. SIGNIFICANCE NCTD is a synthetic, small-molecule compound possessing anti-angiogenetic activity with potential use in anti-cancer therapy as an anti-metastatic and anti-angiogenic agent.

Synthesis and anticancer activity of a novel series of 9-O-substituted berberine derivatives: A lipophilic substitute role

To alter its hydrophobicity, a series of compounds bearing 9-O-alkyl- or 9-O-terpenyl- substituted berberine were synthesized and evaluated for anticancer activity against human cancer HepG2 and HT29 cell lines. We found that the lipophilic substitute of 9-O-alkyl- and 9-O-terpenyl berberine derivatives plays a role in inhibiting the human cancer cell growth and its activity could be maximized with the optimized substitute type and chain length. Most strikingly, nonetheless, of the six compounds prepared, sample 8, a farnesyl 9-O-substituted berberine, showed either comparable or better cytotoxic activity against human cancer HepG2 cell line than that of berberine. Compound 8 had also shown a 104-fold antiproliferation activity in compare with berberine against human hepatoma HepG2 cell lines after 48 incubation hours. Further, in Hoechst 33258 and annexin V-FITC/PI staining analyses it induced apoptosis in HepG2 cells at lower concentration than that of berberine for 24h. Take all; farnesyl 9-O-substituted berberine could be a potential candidate for new anticancer drug development.

Heart rate variability predicts short-term outcome for successfully resuscitated patients with out-of-hospital cardiac arrest

OBJECTIVE To assess the possibility of heart rate variability (HRV) measures as predictors of 24-h mortality in successfully resuscitated patients with out-of-hospital cardiac arrest (OHCA). METHODS This prospective cohort study was conducted at a 40-bed emergency department (ED) of a university-affiliated medical centre. Adult patients with OHCA who were successfully resuscitated were consecutively enrolled over an 18-month period. A 10-min electrocardiogram was recorded for retrospective off-line HRV analysis 30-60 min after the return of spontaneous circulation and further correlated with 24-h mortality of the patients. RESULTS Sixty-nine patients aged 31-82 years who met the inclusion criteria were enrolled. According to the 24-h mortality, the patients were categorised into non-survivors (n=28) and survivors (n=41) groups. The HRV measures were compared between these two groups. The low-frequency power (LFP), normalized LFP (nLFP) and low-/high-frequency power ratio in the non-survivors were significantly lower than those of the survivors, whereas root mean square successive difference, high-frequency power (HFP), HFP/tidal volume, normalized HFP (nHFP), and nHFP/tidal volume in the non-survivors were significantly higher than those of the survivors. Multiple logistic regression model identified nLFP as the independent variable to predict 24-h mortality (odds ratio, 1.354; 95% confidence interval [CI], 1.124-1.632; p=0.001). Receiver operating characteristic area for nLFP in the prediction of 24-h mortality was 0.946 (95% CI, 0.897-0.995; p<0.001). CONCLUSIONS HRV measures, especially the nLFP, may be used as predictors of 24-h mortality for successfully resuscitated patients with OHCA in the ED.

Norcantharidin induces cell cycle arrest and inhibits progression of human leukemic Jurkat T cells through mitogen-activated protein kinase-mediated regulation of interleukin-2 production.

Norcantharidin (NCTD) is a potential anti-cancer agent that inhibits proliferation and induces cell death through regulation of mitogen-activated protein kinases (MAPK). This study examined the effect of NCTD on tumor cells by using a model of phorbol 12-myristate 13-acetate plus ionomycin (PMAI)-activated leukemia Jurkat T cells. The results showed that NCTD significantly inhibited the viability of cells with and without PMAI treatment. NCTD induced cell cycle arrest at G2/M phase, down-regulated the expression of calcineurin and, by itself or in combination with Cyclosporine A, reduced calcineurin phosphatase activity. Furthermore, NCTD up-regulates the expression of phosphorylated (p)-P38 and p-ERK1/2, but not JNK in PMAI-activated Jurkat T cells, in accordance with the alteration in viability. Regarding major cytokine and chemokine secretion profile, NCTD attenuates PMAI-augmented production of IL-2, but slightly increases or has no effect on TNF-α and IL-8. By blockade of various MAPK, NCTD regulates PMAI-augmented IL-2 production through activation of P38 and ERK1/2, in accordance with the aforementioned MAPK expression. In conclusion, NCTD inhibited IL-2 production in PMAI-activated human leukemia Jurkat T cells through activation of P38 and ERK1/2, suggesting that NCTD might have the potential of being used as a chemopreventive agent to inhibit tumor progression in the future.