Pharmacological evaluation of a new Ca2+ antagonist, 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8): studies in smooth muscles

The pharmacology of 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8) has been studied using guinea pig ileum and vas deferens preparations. TMB-8 inhibited responses to drugs that excite specific receptors (acetylcholine and norepinephrine) as well as to agents whose actions are not mediated via specific receptors (KCl and BaCl₂) with ID₅₀'s of 3.8 × 10^?6 to 1 × 10^?4 M. TMB-8 inhibited responses to acetylcholine, norepinephrine, nicotine, dimethylphenylpiperazinium and KCl in an insurmountable manner in the guinea pig ileum, while responses to BaCl₂ were inhibited in a competitive manner. Increasing Ca²⁺ concentrations of the bathing medium from 1.35 to 5.40 mM effectively antagonized the TMB-8 inhibition of responses to KCl in the guinea pig ileum and vas deferens preparations. These results indicate that TMB-8 may produce its inhibitory effects in smooth muscle by interfering with the availability of Ca²⁺ for muscle contraction by blocking the Ca²⁺ release from intracellular bound stores.     

Prognostic significance of clonal diversity of immunoglobulin gene rearrangements in patients with diffuse large B-cell lymphoma

Clonal diversity of the immunoglobulin (Ig) gene rearrangement represents the oligoclonality of B-cell neoplasm, and has been shown to be a marker for poor prognosis in acute lymphoblastic leukemia. However, no previous report has addressed its prognostic impact in diffuse large B-cell lymphoma (DLBCL). We investigated the clinical significance of clonal diversity in DLBCL patients. Lymph node samples from 98 DLBCL patients were examined for Ig heavy and light chain gene rearrangements using Southern blot analysis. Clonal diversity was defined as oligoclonality detected on Southern blotting as previously described, and PCR analysis for IgH oligoclonality was performed on parts of DLBCL samples with clonal diversity for confirming the Southern blot analysis results. We found that clonal diversity could be detected in 36 (36.7%) of DLBCL patients, and PCR analysis showed concordant results. Regarding the clinical relevance, clonal diversity was significantly associated with relapse or refractory disease. Survival analysis showed that clonal diversity is an independent prognostic factor in DLBCL (p=0.05, Cox's proportional hazard method), and stratified analyses found the most significant subgroup is the high-intermediate risk category (p=0.01, log-rank test). We conclude that clonal diversity of Ig gene rearrangements is associated with a high risk of relapse or refractory disease in DLBCL patients. It is also a factor of poor prognosis in DLBCL, especially for high-intermediate risk category.     

Cyanidin 3-glucoside and peonidin 3-glucoside inhibit tumor cell growth and induce apoptosis in vitro and suppress tumor growth in vivo

Dietary polyphenols, including anthocyanins, are suggested to be involved in the protective effects of fruits and vegetables against cancer. However, anticancer effects of peonidin 3-glucoside have not been clearly demonstrated, with only limited studies being available concerning the inhibitory effect of cyanidin 3-glucoside for tumor cell growth. Therefore, in this study, we have isolated and identified the two bioactive compounds, peonidin 3-glucoside and cyanidin 3-glucoside, from Oryza sativa L. indica, to treat various cancer cells. The results showed that, among analyzed cell lines, HS578T was the most sensitive to peonidin 3-glucoside and cyanidin 3-glucoside. Treatment with peonidin 3-glucoside or cyanidin 3-glucoside resulted in a strong inhibitory effect on cell growth via G2/M arrest. Regarding cell cyclerelated proteins, peonidin 3-glucoside treatment resulted in down-regulation of protein levels of cyclin-dependent kinase (CDK)-1, CDK-2, cyclin B1, and cyclin E, whereas cyanidin 3-glucoside could decrease the protein levels of CDK-1, CDK-2, cyclin B1, and cyclin D1. In addition, cyanidin 3-glucoside or peonidin 3-glucoside also induced caspase-3 activation, chromatin condensation, and cell death. Furthermore, anthocyanins from O. sativa L. indica were evidenced by their inhibition on the growth of Lewis lung carcinoma cells in vivo.     

Neutralizing antibody response and SARS severity

Using the Taiwan nationwide laboratory-confirmed severe acute respiratory syndrome (SARS) database, we analyzed neutralizing antibody in relation to clinical outcomes. With a linear mixed model, neutralizing antibody titer was shown to peak between week 5 and week 8 after onset and to decline thereafter, with a half-life of 6.4 weeks. Patients with a longer illness showed a lower neutralizing antibody response than patients with a shorter illness duration (p = 0.008). When early responders were compared with most patients, who seroconverted on and after week 3 of illness, the small proportion (17.4%) of early responders (antibody detectable within 2 weeks) had a higher death rate (29.6% vs. 7.8%) (Fisher exact test, p = 0.004), had a shorter survival time of <2 weeks (Fisher exact test, p = 0.013), and were more likely to be > 60 years of age (Fisher exact test, p = 0.01). Our findings have implications for understanding the pathogenesis of SARS and for SARS vaccine research and development.     

Variable pump flow-based Doppler ultrasound method: a novel approach to the measurement of access flow in hemodialysis patients

Decreasing vascular access flow (Qa) is an important predictor of future access thrombosis and malfunction for hemodialysis (HD) patients. Among all of the methods for determining Qa, the variable pump flow (VPF) Doppler method measures Qa according to the change in Doppler signal between the arterial and the venous needles under different pump flow. After this technique was combined with spectral analysis of Duplex Doppler imaging, the variable pump flow-based Doppler ultrasound method (VPFDUM) for Qa measurement was developed. This study compared the reproducibility and correlation of Qa measurements for three different methods-VPFDUM, ultrasound dilution method (UDM), and conventional Doppler ultrasound method (CDUM)-in 55 HD patients. The mean value of Qa by VPFDUM (870.8 +/- 412.0 ml/min) was close to that by UDM (868.6 +/- 417.9 ml/min) but higher than that by CDUM (either of the above values versus 685.1 +/- 303.6 ml/min; P < 0.005). The mean values of coefficient of variation were similar by VPFDUM (1.6%) and UDM (1.4%) but lower than that by CDUM (either of the above values versus 6.8%; P < 0.01). The correlation coefficient and intraclass correlation coefficient of the repeated Qa measurements by VPFDUM (0.985 and 0.993; P < 0.001) were also similar to those by UDM (0.992 and 0.995; P < 0.001) but slightly higher than those by CDUM (0.917 and 0.948; P < 0.005). Either the reproducibility of VPFDUM (r=0.98, P < 0.0001) or the correlation between VPFDUM and UDM (r=0.99, P < 0.0001) in Qa measurements is good. The unassisted patency of vascular access at 6 mo was significantly poorer in patients with Qa <500 ml/min than those with Qa >500 ml/min (13.6% versus 92.2%; P < 0.0001). In conclusion, VPFDUM is a noninvasive, accurate, and reliable procedure for Qa measurement and prediction of the prognosis of vascular access in HD patients.     

Correlation of the dysmetabolic risk factors with different anthropometric measurements

Metabolic syndrome is a common disorder in Taiwan. For this study 431 subjects were randomly selected from visitors to the Department of Health Management. Blood pressure, blood glucose, lipid, uric acid levels and anthropometric measurements with immunoreactive insulin (IRI) and leptin levels were all correlated. We randomly selected 431 subjects who visited the Department of Health Management. Whole body three-dimensional (3-D) laser scanner scans were employed for the anthropometric measurements. The metabolic index (MI) was designed using anthropometric parameters. Of the 431 subjects, 50% had displayed a body mass index (BMI) equal to or exceeding 25 kg/m2. Pearson correlation coefficient and multiple regression analysis revealed that MI constituted another index for correlating metabolic parameters by comparing MI with BMI and waist circumference to hip circumference ratio (WHR). Most data related to metabolic syndrome showed statistically significant differences between high and low IRI groups, comprising uric acid, total cholesterol, fasting plasma glucose, triglyceride, LDL, Chol/HDL ratio, and LDL/HDL ratio. Both IRI and leptin revealed statistical association with BMI, WHR, waist cross section area to hip cross section area ratio (WHAR), and MI in the study. Hypercholesterolemia appeared in 14.6% of the subjects. Elevated low-density lipoprotein (> or = 130 mg/dL) affected 36.9% of the subjects. In conclusion, MI calculated from 3-D body scanner correlated with many important metabolic risk factors and associated with clinical disorders like DM, hyperlipidemia, hyperuricemia and hypertension.