Evaluation of exposure to carbon monoxide associated with passive smoking

The current study measured breath carbon monoxide (CO) concentrations prior to and at prescribed time intervals after exposure to passive smoking under controlled conditions, along with the air CO concentration in the exposure room during the exposure periods. The postexposure breath CO levels were 1.4-2.7 times higher than the background breath CO levels after 30 min of exposure, yet only slightly higher after 10 min of exposure, thereby confirming that exposure to CO from passive smoking causes a significant body burden of CO. The air CO concentration gradually increased during the burning of a cigarette(s), regardless of the exposure duration, whereas it slightly decreased after burning. However, the pattern of breath CO decay was similar for the two different types of exposure (during and after a cigarette(s)) in each subject. The decrease in the postexposure alveolar CO concentrations was slow even in the early phase of the decay curves, indicating a monocompartment uptake and elimination model for the human body. The half-lives (78-277 min) estimated in the present study were comparable to those reported in previous studies associated with CO exposure from active smoking or other activities. The current study also evaluated the CO exposure of visitors and workers at three different types of recreation facility (bars, Internet cafes, and billiard halls) typically associated with passive smoking. The results confirmed that passive smoking is the major contributor to the CO exposure of nonsmoking visitors in a recreation environment. In addition, workplace exposure to CO from passive smoking was found to be the most important contributor to the daily CO exposure of nonsmoking recreation workers.     

Transthoracic echocardiography and carotid Doppler ultrasound for detection of cardiac and carotid artery disease in patients with acute retinal artery obstruction

We reviewed the medical records of patients with acute retinal artery obstruction (RAO) and evaluated the importance of transthoracic echocardiography (TTE) and carotid Doppler ultrasound in determining causes of cardiac and carotid artery origin in RAO. A retrospective case study conducted in the Department of Ophthalmology, Inha University Hospital, Korea comprised 26 patients presenting with acute RAO who underwent systemic evaluation, TTE and carotid Doppler ultrasound between June 1, 1997 and December 31, 2003. Among these 26 patients, abnormal cardiac findings were detected in 12 (46%) and abnormal carotid findings in 4 (15%). Furthermore, other risk factors for RAO were found in 2 (8%) and stroke broke out within 7 months after experiencing RAO in 4 (15%) of the 26 patients. In patients with acute RAO, TTE and carotid Doppler ultrasound play an important role in pinpointing the origins of retinal emboli. It is thought that TTE and carotid Doppler ultrasound may be essential examinations for determining the underlying cause, planning treatment strategies, and preventing stroke and death.     

Ginseng saponins induce store-operated calcium entry in Xenopus oocytes

1 We investigated the effect of the active ingredients of Panax ginseng, ginsenosides, on store-operated Ca2+ entry (SOCE) using a two-electrode voltage clamp technique in Xenopus oocytes in which SOCE is monitored through Ca(2+)-activated Cl- currents. 2 Under hyperpolarizing voltage clamp conditions, treatment with ginsenosides produced a biphasic Ca(2+)-activated Cl- current consisting of a rapid transient inward current and a slowly developing secondary sustained inward current. The transient inward current was inactivated rapidly, whereas the sustained inward current persisted for nearly 10 min. The effect of ginsenosides on the biphasic current was dose-dependent and reversible. The EC50 was 42.8+/-11.6 and 46.6+/-7.1 microg ml(-1) for the transient and sustained inward current, respectively. 3 In the absence of extracellular Ca2+ ginsenosides induced only a transient inward current but in the presence of extracellular Ca2+ ginsenosides induced the biphasic current. Magnitudes of the sustained currents were dependent on extracellular Ca2+ concentration. Sustained inward current induced by ginsenosides, but not transient inward current, and ginsenoside-induced store-operated Ca2+ (SOC) currents (ISOC) were blocked by La3+, a Ca2+ channel blocker, suggesting that the sustained inward current and ISOC was derived from an influx of extracellular Ca2+. 4 Treatment with 2-APB and heparin, which are IP3 receptor antagonists, inhibited the ginsenoside-induced biphasic current. Treatment with the PLC inhibitor, U73122, also inhibited the ginsenoside-induced biphasic current. Intraoocyte injection of ATP-gammaS, but not adenylyl AMP-PCP, induced a persistent activation of ginsenoside-induced sustained current but did not affect the transient current. 5 In rat hippocampal neurons, ginsenosides inhibited both carbachol-stimulated intracellular Ca2+ release and intracellular Ca2+ depletion-activated SOCE. 6 These results indicate that ginsenoside might act as a differential regulator of intracellular Ca2+ levels in neurons and Xenopus oocytes.     

Pharmacokinetic study of mycophenolic acid in Korean kidney transplant patients

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC.     

4-Acetyl-12,13-epoxyl-9-trichothecene-3, 15-diol from Isaria japonica mediates apoptosis of rat bladder carcinoma NBT-II cells by decreasing anti-apoptotic Bcl-2 expression and increasing pro-apoptotic Bax expression

We studied the effect of 4-acetyl-12,13-epoxyl-9-trichothecene-3, 15-diol (AETD) isolated from Isaria japonica, one of the most popular Chinese fungal medicines, on the induction of apoptosis in rat bladder carcinoma NBT-II cells. AETD was cytotoxic to NBT-II cells, and this cytotoxic effect appears to be attributed to its induction of apoptotic cell death, as AETD induced nuclear morphological changes and internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells and activity of caspase-3. AETD treatment also decreased the expression of the anti-apoptotic protein Bcl-2 and increased the expression of the pro-apoptotic protein Bax. These results provide important information in understanding the mechanism(s) of AETD-induced apoptosis.     

Isolation and anticomplement activity of compounds from Dendropanax morbifera

Dendropanax morbifera Leveille (Araliaceae) is used in Korea for a variety of disease, such as migraine headache and dysmenorrheal. A new polyacetylene (1) and six known compounds (2–7) were isolated from the leaves of this plant by conventional chromatographic techniques. The structure of the new polyacetylene (1) was determined as (9Z,16S)-16-hydroxy-9,17-octadecadiene-12,14-diynoic acid by spectroscopic means including 2D NMR, which comprised the determination of a chiral by modified Mosher’s ester method. Compounds 1–7 were investigated in vitro for their anticomplement activity against the classical pathway of the complement system. Of these, compound 1 showed significant anticomplement activity with 50% inhibitory concentration (IC₅₀) value of 56.98 μM, whereas compounds 2–7 were inactive.     

Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy

BACKGROUND: The objective of this study was to assess the biologic activity of rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist that has been approved to treat type 2 diabetes, in men with recurrent prostate carcinoma using change in prostate specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. METHODS: Men with histologically confirmed prostate carcinoma, no recent hormone therapy, a rising serum PSA level after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases were assigned randomly to receive either oral rosiglitazone (4 mg twice daily) or placebo. The treatment was continued until the men developed disease progression or adverse effects. A positive outcome was defined as a posttreatment PSADT > 150% the baseline PSADT and no new metastases. RESULTS: One hundred six men were enrolled. The median treatment duration was 315 days for men in the placebo group and 338 days for men in the rosiglitazone group (P = 0.28). Forty percent of men in the in the placebo group and 38% of men in the rosiglitazone group had a posttreatment PSADT > 150% of the baseline PSADT and no new metastases (P = 1.00). In exploratory analyses, the rate of a positive outcome remained higher than expected in the placebo group, even when a positive outcome was redefined using more stringent criteria. The time to disease progression was similar between the groups. CONCLUSIONS: Rosiglitazone did not increase PSADT or prolong the time to disease progression more than placebo in men with a rising PSA level after radical prostatectomy and/or radiation therapy. The unexpected discordance between baseline and posttreatment PSADT in the placebo group reinforced the importance of randomized controlled trials in this setting.     

Human CTLs to wild-type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells

Vaccine therapy for prostate and breast cancer may have potential for treating these major causes of death in males and females, respectively. Critical to the development of tumor-specific vaccines is finding and characterizing novel antigens to be recognized by CD8(+) T cells. To define new CD8(+) T-cell tumor antigens, we determined two wild-type HLA-A2 epitopes from a recently found tumor-associated protein, TARP (T-cell receptor gamma alternate reading frame protein), expressed in prostate and breast cancer cells. We were also able to engineer epitope-enhanced peptides by sequence modifications. Both wild-type and enhanced epitopes induced peptide-specific CD8(+) T-cell responses in A2K(b) transgenic mice. In vitro restimulation of human CD8(+) T cells from a prostate cancer patient resulted in CD8(+) T cells reactive to the peptide epitopes that could lyse HLA-A2(+) human breast cancer cells (MCF-7) expressing TARP. Epitope-specific human CD8(+) T cells were also enumerated in patients' peripheral blood by tetramer staining. Our data suggest that HLA-A2-binding TARP epitopes and enhanced epitopes discovered in this study could be incorporated into a potential vaccine for both breast and prostate cancer.     

Tissue inhibitors of metalloproteinase 2 inhibits endothelial cell migration through increased expression of RECK

The antiangiogenic function of the tissue inhibitors of metalloproteinases (TIMPs) has been attributed to their matrix metalloproteinase inhibitory activity. Here we demonstrate that TIMP-1 but not Ala+TIMP-1 inhibits both basal and vascular endothelial growth factor (VEGF)-stimulated migration of human microvascular endothelial cells (hMVECs), suggesting that this effect is dependent on direct inhibition of matrix metalloproteinase (MMP) activity. In contrast, TIMP-2 and mutant Ala+TIMP-2, which is devoid of MMP inhibitory activity, block hMVEC migration in response to VEGF-A stimulation. TIMP-2 and Ala+TIMP-2 also suppress basal hMVEC migration via a time-dependent mechanism mediated by enhanced expression of RECK, a membrane-anchored MMP inhibitor, which, in turn, inhibits cell migration. TIMP-2 treatment of hMVECs increases the association of Crk with C3G, resulting in enhanced Rap1 activation. hMVECs stably expressing Rap1 have increased RECK expression and display reduced cell migration compared with those expressing inactive Rap1(38N). RECK-null murine embryo fibroblasts fail to demonstrate TIMP-2-mediated decrease in cell migration despite activation of Rap1. TIMP-2-induced RECK decreases cell-associated MMP activity. Anti-RECK antibody increases MMP activity and reverses the TIMP-2-mediated reduction in cell migration. The effects of TIMP-2 on RECK expression and cell migration were confirmed in A2058 melanoma cells. These results suggest that TIMP-2 can inhibit cell migration via several distinct mechanisms. First, TIMP-2 can inhibit cell migration after VEGF stimulation by direct inhibition of MMP activity induced in response to VEGF stimulation. Secondly, TIMP-2 can disrupt VEGF signaling required for initiation of hMVEC migration. Third, TIMP-2 can enhance expression of RECK via Rap1 signaling resulting in an indirect, time-dependent inhibition of endothelial cell migration.