Application of high-dose propofol during ischemia improves postischemic function of rat hearts: effects on tissue antioxidant capacity

Previous studies have shown that reactive oxygen species mediated lipid peroxidation in patients undergoing cardiac surgery occurs primarily during cardiopulmonary bypass. We examined whether application of a high concentration of propofol during ischemia could effectively enhance postischemic myocardial functional recovery in the setting of global ischemia and reperfusion in an isolated heart preparation. Hearts were subjected to 40 min of global ischemia followed by 90 min of reperfusion. During ischemia, propofol (12 microg/mL in saline) was perfused through the aorta at 60 microL/min. We found that application of high-concentration propofol during ischemia combined with low-concentration propofol (1.2 microg/mL) administered before ischemia and during reperfusion significantly improved postischemic myocardial functional recovery without depressing cardiac mechanics before ischemia, as is seen when high-concentration propofol was applied prior to ischemia and during reperfusion. The functional enhancement is associated with increased heart tissue antioxidant capacity and reduced lipid peroxidation. We conclude that high-concentration propofol application during ischemia could be a potential therapeutic and anesthetic strategy for patients with preexisting myocardial dysfunction.     

Dose-dependent protection of cardiac function by propofol during ischemia and early reperfusion in rats: effects on 15-F2t-isoprostane formation

We examined the effects of propofol (2,6-diisopropylphenol) on functional recovery and 15-F2t-isoprostane generation during ischemia-reperfusion in Langendorff-perfused rat hearts. Before the induction of 40 min of global ischemia, hearts were perfused (10 min) with propofol at 5 (lo-P) or 12 microg/mL (hi-P) in saline or with saline only (control). During ischemia, saline, lo-P, or hi-P was perfused through the aorta at 60 microL/min. During the first 15 min of reperfusion, propofol (5 or 12 microg/mL) was continued, followed by perfusion with 5 microg/mL propofol for 75 min in both propofol-treated groups. After 90 min of reperfusion (Rep-90), heart tissues were harvested for assessment of antioxidant status. In hi-P, we observed increased latency to and greater reduction of ischemic contracture relative to the lo-P or control groups. 15-F2t-Isoprostane concentrations increased during ischemia and were significantly lower in hi-P and lo-P than in control (P < 0.01). At Rep-90, myocardial functional recovery was greater in both propofol-treated groups relative to control, and it correlated positively with tissue antioxidant capacity preservation. Tissue antioxidant capacity was better preserved in hi-P than in lo-P treatment (P < 0.05). We conclude that oxidant injury occurs during ischemia and reperfusion, and propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation.     

Inhibitory effects of propofol on neuron firing activities in the rostral ventrolateral medulla

The effect of propofol on neuronal activity in the rostral ventrolateral medulla (RVLM) is not well established. Therefore, we performed extracellular recording on neurons of the RVLM to investigate neuronal activity before and after administration of intravenous propofol. The mean systemic arterial pressure (MSAP), heart rate and integrated neuronal firing rate (INFR) in the RVLM were continuously recorded in anesthetized cats before and after intravenous injection of 2 mg/kg propofol or supplemental injections of 1, 2 and 4 mg/kg propofol that were given respectively. Additionally, we compared the MSAP, heart rate (HR), and INFR in the RVLM following intravenous injection of 2 mg/kg propofol or 12.5 microg/kg nitroprusside. Neuronal firing was dose-dependently and reversibly inhibited after the supplemental doses of 1, 2 and 4 mg/kg propofol. The control INFR was 14.2 +/- 9.9 Hz, and this decreased to 12.1 +/- 9.4 Hz after the first dose of propofol (P = 0.085 vs. control), and further decreased to 9.3 +/- 7.7 Hz (P = 0.001 vs. control) and 7.5 +/- 7.7 Hz (P < 0.001 vs. control) after the second and third doses of propofol, respectively. Besides, SAP and HR were dose-dependently decreased by propofol as well. However, the effects of propofol and nitroprusside on neuronal activity in the RVLM differed. Propofol inhibited neuronal firing, whereas nitroprusside activated neuronal firing. In conclusion, propofol may dose-dependently inhibit spontaneous neuronal activity and the baroreflex in the RVLM.     

Time-resolved fluoroimmunoassays of the complete set of secreted phospholipases A2 in human serum

Time-resolved fluoroimmunoassays (TR-FIA) were developed for all human secreted phospholipases A(2) (PLA(2)), viz. group (G) IB, GIIA, GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein. Antibodies were raised in rabbits against recombinant human PLA(2) proteins and used in sandwich-type TR-FIAs as both catching and detecting antibodies, the latter after labeling with Europium. The antibodies were non-cross-reactive. The analytical sensitivities were 1 microg/L for the TR-FIA for GIB PLA(2), 1 microg/L (GIIA), 35 microg/L (GIID), 3 microg/L (GIIE), 4 microg/L (GIIF), 14 microg/L (GIII), 11 microg/L (GV), 2 microg/L (GX), 92 microg/L (GXIIA) and 242 microg/L (GXIIB). All secreted PLA(2)s were assayed by these TR-FIAs in serum samples from 34 patients (23 men and 11 women, mean age 53.2 years) treated in an intensive care unit for septic infections, and in control samples from 28 volunteer blood donors (14 men and 14 women, mean age 57.0 years). Five serum samples (3 in the sepsis group and 2 in the blood donor group) gave high TR-FIA signals that were reduced to background (blank) levels by the addition of non-immune rabbit IgG to the sera. This reactivity was assumed to be due to the presence of heterophilic antibodies in these subjects. In all other subjects, including septic patients and healthy blood donors, the TR-FIA signals for GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein were at background (blank) levels. Four patients in the sepsis group had pancreatic involvement and elevated concentration of GIB PLA(2) in serum (median 19.0 microg/L, range 13.1-33.7 microg/L, n = 4) as compared to the healthy blood donors (median 1.8 microg/L, range 0.8-3.4 microg/L, n = 28, P < 0.0001). The concentration of GIIA PLA(2) in the sera of septic patients (median 315.7 microg/L, range 15.9-979.6 microg/L, n = 34) was highly elevated as compared to that of the blood donors (median 1.8 microg/L, range 0.8-5.8 microg/L, n = 28, P < 0.0001). Our current results confirmed elevated concentrations of GIB and GIIA PLA(2) in the sera of patients suffering from acute pancreatitis or septic infections, respectively, as compared to healthy subjects. However, in the same serum samples, the concentrations of the other secreted PLA(2)s, viz. GIID, GIIE, GIIF, GIII, GV, GX and GXIIA PLA(2) and the GXIIB PLA(2)-like protein were below the respective analytical sensitivities of the TR-FIAs. It is concluded that generalized bacterial infections do not lead to elevated serum levels of GIIE, GIIF, GIII, GV and GX PLA(2)s above the detection limits of the current TR-FIAs.     

异丙酚对人肺血管内皮细胞中ACEⅡ表达的影响

目的:观察异丙酚对人肺动脉内皮细胞中ACE2的影响。方法:以人肺动脉内皮细胞为研究对象,利用Real-time PCR检测不同浓度(1、10、20、40、50μmol/L)异丙酚在不同时间点(6、12、18、24、30h)对HPAEC中ACE2 mRNA表达的影响;Western Blot检测不同浓度(1、10、20、40、50μmol/L)异丙酚对HPAEC中ACE2蛋白表达的影响;观察磷脂酰肌醇-3-激酶(PI3K)抑制剂LY294002对异丙酚调节HPAEC中ACE2 mRNA表达的影响。结果:异丙酚呈剂量和时间依赖性可提高人肺动脉内皮细胞ACE2mRNA水平(P0.05)。但异丙酚浓度为1μmol/L时对ACE2 mRNA水平表达无明显影响(P0.05)。Western Blot检测结果显示异丙酚可增加HPAEC中ACE2蛋白的表达,且在24 h内具有剂量依赖性。异丙酚在24h时剂量依赖性提高Akt的磷酸化,而LY294002可逆转异丙酚对Akt磷酸化的影响。结论:异丙酚可分别通过PI3K/Akt信号途径上调ACE2的表达,使RAS轴处在动态平衡中,从而发挥舒张血管和镇痛作用。     

Inhibitory effects of propofol on supraoptic nucleus neurons of rat hypothalamus in vitro

To investigate the effects of novel intravenous general anesthetic propofol on membrane electrophysiological characteristics and action potential (AP) of the supraoptic nucleus (SON) neurons and possible ionic mechanisms, intracellular recordings were conducted in SON neurons from the coronal hypothalamic slice preparation of adult male Sprague Dawley (SD) rats. The results showed that bath application of 0.1 mmol/L propofol induced a significant decline in resting potential (P < 0.01), and higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased time constant and slope resistance of cell membrane (P < 0.01). Under the hyperpolarizing current pulses exceeding 0.5 nA, an anomalous rectification was induced by hyperpolarization-activated cation channel (I(h) channel) in 11 out of 18 tested SON neurons. Bath of propofol reversibly decreased the anomalous rectification. Moreover, 0.1 mmol/L propofol elevated threshold level (P < 0.01) and decreased Max L. slope (P < 0.05) of the spike potential in SON neurons. Interestingly, 0.3 and 1.0 mmol/L propofol nullified APs in 6% (1/18) and 71% (12/17) tested SON neurons, respectively. In the SON neurons where APs were not nullified, propofol (0.3 mmol/L) decreased the amplitude of spike potential (P < 0.05). The higher concentrations of propofol (0.3 and 1.0 mmol/L) decreased firing frequencies evoked by depolarizing current pulses (0.1-0.7 nA), and shifted the current intensity-firing frequency relation curves downward and to the right. These results suggest that propofol decreases the excitability of SON neurons by inhibiting I(h) and sodium channels.     

Propofol Pharmacokinetics and Estimation of Fetal Propofol Exposure during Mid-Gestational Fetal Surgery: A Maternal-Fetal Sheep Model

Background

Measuring fetal drug concentrations is extremely difficult in humans. We conducted a study in pregnant sheep to simultaneously describe maternal and fetal concentrations of propofol, a common intravenous anesthetic agent used in humans. Compared to inhalational anesthesia, propofol supplemented anesthesia lowered the dose of desflurane required to provide adequate uterine relaxation during open fetal surgery. This resulted in better intraoperative fetal cardiac outcome. This study describes maternal and fetal propofol pharmacokinetics (PK) using a chronically instrumented maternal-fetal sheep model.

Methods

Fetal and maternal blood samples were simultaneously collected from eight mid-gestational pregnant ewes during general anesthesia with propofol, remifentanil and desflurane. Nonlinear mixed-effects modeling was performed by using NONMEM software. Total body weight, gestational age and hemodynamic parameters were tested in the covariate analysis. The final model was validated by bootstrapping and visual predictive check.

Results

A total of 160 propofol samples were collected. A 2-compartment maternal PK model with a third fetal compartment appropriately described the data. Mean population parameter estimates for maternal propofol clearance and central volume of distribution were 4.17 L/min and 37.7 L, respectively, in a typical ewe with a median heart rate of 135 beats/min. Increase in maternal heart rate significantly correlated with increase in propofol clearance. The estimated population maternal-fetal inter-compartment clearance was 0.0138 L/min and the volume of distribution of propofol in the fetus was 0.144 L. Fetal propofol clearance was found to be almost negligible compared to maternal clearance and could not be robustly estimated.

Conclusions

For the first time, a maternal-fetal PK model of propofol in pregnant ewes was successfully developed. This study narrows the gap in our knowledge in maternal-fetal PK model in human. Our study confirms that maternal heart rate has an important influence on the pharmacokinetics of propofol during pregnancy. Much lower propofol concentration in the fetus compared to maternal concentrations explain limited placental transfer in in-vivo paired model, and less direct fetal cardiac depression we observed earlier with propofol supplemented inhalational anesthesia compared to higher dose inhalational anesthesia in humans and sheep.     

Batch and continuous removal of arsenic using hyacinth roots

Arsenic is considered a primary pollutant in drinking water because of its high toxicity. The unique property of water hyacinth roots (Eichhornia crassipes) to remove heavy metals is of great signiicance for the development of a cost-effective phytoremediation technology. An experimental test program was conducted at the United States Environmental Protection (USEPA) Test and Evaluation (T&E) Facility in Cincinnati, Ohio, to investigate the potential of water hyacinth roots to remove arsenic from spiked drinking water samples. Water hyacinth roots were washed, dried, and powdered to provide dried hyacinth roots (DHR) for batch and continuous column experiments, Various quantities of DHR were added to water spiked with 300 micrograms per liter (microg/L) arsenic. A concentration of 20 g/L DHR was found adequate for greater than 90% arsenic removal in the batch tests. Based on the batch test results, continuous column experiments were performed using a 2-L column. In a continuous system, 15 L of water containing 300 microg/L arsenic were treated to below 20 microg/L using 50 g DHR, and 44 L of water containing 600 microg/L arsenic were treated to below 20 microg/L using 100 g DHR, giving a specific accumulation rate of approximately 260 microg As/g DHR.     

Chromium-induced glucose uptake, superoxide anion production, and phagocytosis in cultured pulmonary alveolar macrophages of weanling pigs

The dose-dependent effects of chromium chloride (CrCl₃) and chromium picolinate (CrPic) were evaluated for their glucose uptake, superoxide anion (O ₂ ⁻ ) production, activity of glucose-6-phosphate dehydrogenase, and phagocytosis of incubated pulmonary alveolar macrophages in medium containing no or 5 × 10⁻⁸ M insulin. Glucose uptake was found to increase in cells treated with 20 μg/L CrCl₃. Incubation with 20 μg/L of CrPic enhanced glucose uptake and O ₂ ⁻ production in an insulin-dependent manner. However, the inclusion of CrPic to 100 μg/L in the medium absent of insulin also increased O ₂ ⁻ production. The activity of glucose-6-phosphate dehydrogenase was not affected by either the addition of Cr or insulin. The phagocytosis of Escherichia coli by macrophages was enhanced significantly (p<0.05) in medium containing 10–100 μg/L CrCl₃ or 20–100 μg/L CrPic in the presence of insulin. These results suggest that the addition of 10–20 μg/L CrCl₃ enhances directly the cellular activity of macrophages, whereas the effect of CrPic requires the cooperative action of insulin in enhancing their glucose uptake and phagocytosis.     

Propofol-mediated cardioprotection dependent of microRNA-451/HMGB1 against myocardial ischemia-reperfusion injury

Administration of propofol at the time of reperfusion has shown to protect the heart from ischemia and reperfusion (I/R) injury. The aim of the present study was to investigate the molecular mechanism underling the cardioprotective effect of propofol against myocardial I/R injury (MIRI) in vivo and in vitro. Rat heart I/R injury was induced by ligation of the left anterior descending (LAD) artery for 30 min followed by 2-hr reperfusion. Propofol pretreatment (0.01 mg/g) was performed 10 min before reperfusion. In vitro MIRI was investigated in cultured cardiomyocytes H9C2 following hypoxia/reoxygenation (H/R) injuries. Propofol pretreatment in vitro was achieved in the medium supplemented with 25 μmol/L propofol before H/R injuries. Propofol pretreatment significantly increased miRNA-451 expression, decreased HMGB1 expression, reduced infarct size, and I/R-induced cardiomyocyte apoptosis in rat hearts undergoing I/R injuries. Knockdown of miRNA-451 48 hr before I/R injury was found to increase HMGB1 expression, infarct size, and I/R-induced cardiomyocyte apoptosis in rat hearts in the presence of propofol pretreatment. These in vivo findings were reproduced in vivo that knockdown of miRNA-451 48 hr before H/R injuries increased HMGB1 expression and H/R-induced apoptosis in cultured H9C2 supplemented with propofol. In addition, luciferase activity assays and gain-of-function studies found that propofol could decrease HMGB1, the target of miRNA-541. Taken together our findings provide a first demonstration that propofol-mediated cardioprotection against MIRI is dependent of microRNA-451/HMGB1. The study provides a novel target to prevent I/R injury during propofol anesthesia.     

Urinary hepcidin identifies a serum ferritin cut-off for iron supplementation in young athletes: a pilot study

The use of iron supplements should be a judicious choice, primarily when considering the possible risks deriving from an unjustified treatment. In trained athletes, levels of ferritin between 15 and 30 microg/L are frequently observed. Within this ferritin range, the usefulness of iron supplementation is still controversial. The aim of the present study is to evaluate the clinical usefulness of hepcidin assessment in the analysis of the iron status of young non-anemic athletes. Fifty young athletes were enrolled. The subjects were divided into 4 groups according to their ferritin levels. No statistically significant difference was found regarding hepcidin levels between athletes with ferritin lower than 15 microg/L and those in the 15-30 microg/L range. Similarly, no difference was found between athletes with ferritin higher than 50 microg/L and those in the 30-50 microg/L range. On the contrary, statistically significant differences were found between athletes with ferritin levels ranging from 15 to 30 microg/L and those in the 30-50 microg/L range. The present study suggests that serum ferritin levels below 30 microg/L indicate an asymptomatic iron deficiency status inhibiting hepcidin expression and that 30 microg/L should be considered the ferritin cut-off when considering an iron supplementation in young athletes.     

Plasma molybdenum reflects dietary molybdenum intake

The relationship between plasma molybdenum (Mo) and dietary intake has not been investigated in humans. We developed an isotope dilution method to determine molybdenum in 0.5 mL blood plasma by ICP-MS and conducted a study to determine the effect of dietary intake on plasma molybdenum. Twelve young men consumed a very low Mo diet (22 microg/day) for 24 days while confined to the WHNRC metabolic research unit and plasma molybdenum was monitored. (97)Mo was infused in four of the subjects (Group 1) to follow its clearance from the blood. The other eight remained in unit for 120 days (an additional 96 days). Four consumed the 22 microg/day molybdenum diet for 102 days followed by 467 microg/day for 18 days (Group 2). and four consumed five levels of dietary molybdenum for 24 days each (Group 3). (100)Mo was added to the diet one or more times at each dietary level. Total plasma molybdenum and (100)Mo were monitored throughout the study. Plasma molybdenum in the 12 subjects decreased from 8.2 +/- 0.5 to 6.1 +/- 0.5 nmol/L after 13 days of low molybdenum intake and was 5.1 +/- 0.5 nmol/L after 24 days. In Group 2, average plasma molybdenum was 7.8 +/- 0.9 nmol/L at the beginning of the study, 5.4 +/- 0.4 nmol/L during the 102 days low molybdenum period, and 16.5 +/- 0.6 nmol/L during the high molybdenum period. Plasma molybdenum in Group 3 was 4.2 +/- 2.1 nmol/L at 22 microg/day; 5.8 +/- 2.5 nmol/L at 72 microg/day; 6.6 +/- 2.3 nmol/L at 121 microg/day; 19.7 nmol/L +/-2.1 at 467 microg/day; and 43.9 +/- 2.1 nmol/L at 1490 microg/day. The results demonstrate that, in contrast to most other essential minerals, plasma molybdenum reflects low and high dietary molybdenum intakes within 14 days and may a useful indicator of low and high dietary intakes.     

Pharmacokinetics of prednisone and prednisolone in a case of hypothyroidism: effect of replacement therapy

We found this particular case during the course of a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children. The plasma concentrations of prednisone, its main metabolite prednisolone, and endogenous cortisol were measured by HPLC at selected times during 8-h periods starting at 7:30 a.m. One 9.9-year-old administered prednisone 0.5mg/kg p.o. was found to be hypothyroid (TSH: 351microIU/mL; fT4: <2pg/mL; fT3: <1pg/mL); four age-matched normal boys (aged 6.6+/-4.9 years) served as a control group. In comparison with the controls, the hypothyroid boy showed a marked increase in the total AUC of prednisone (3360microg h/L versus 215+/-83microg h/L) and prednisolone (4040microg h/L versus 724+/-77microg h/L), and an altered pattern of endogenous cortisol, which is known to be impaired in hypothyroid subjects. After 6 months of thyroxine replacement therapy (75microg/day), the AUCs of prednisone and prednisolone returned to normal values (prednisone: 248microg h/L; prednisolone: 528microg h/L), as did the pattern of circadian cortisol secretion. In conclusion, our data indicate that the pharmacokinetics of prednisone and prednisolone can be profoundly altered by hypothyroidism, and subsequently restored by thyroxine replacement therapy.     

Validated method for the simultaneous determination of methadone and its main metabolites (EDDP and EMDP) in plasma of umbilical cord blood by gas chromatography-mass spectrometry

A sensitive and specific GC/MS method for the determination of methadone (MDN) and its two main metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyrroline (EMDP), in plasma samples obtained from venous and arterial umbilical cord blood and maternal blood has been developed, optimized and validated. Specimen preparation includes protein precipitation with acetonitrile and simultaneous solid-phase extraction of the three analytes. Methadone-d9 was used as internal standard for the determination of MDN and EMDP, while EDDP-d3 for EDDP. Limits of detection were 0.6 microg/L for MDN and 0.3 microg/L for EDDP and EMDP, while limits of quantification were 2.0 microg/L for MDN and 1.0 microg/L for EDDP and EMDP. The calibration curves were linear up to 2000 microg/L for MDN and up to 1000 microg/L for EDDP and EMDP. Absolute recovery ranged from 94.8 to 99.7% for all three analytes. Intra- and interday accuracy was less than 5.3 and 5.5%, respectively, while intra- and interday precision was less than 3.5 and 5.0%, correspondingly, for all analytes. The method proved suitable for the determination of MDN and its two main metabolites in plasma samples obtained from umbilical cord and maternal blood of a woman participating in a MDN maintenance program, during the prenatal and postpartum period.     

Effluent recirculation to improve perchlorate reduction in a fixed biofilm reactor

The effect of effluent recirculation on perchlorate reduction in a nominally plug-flow fixed biofilm reactor was studied in two cases: influent concentrations of 10 and 400 microg/L at low hydraulic loading rates (1.9 and 37.5 m(3)/m(2)/day without and with recirculation, respectively) and after a step increase in perchlorate concentration to 1,000 microg/L at the higher hydraulic loading rate (5 and 100 m(3)/m(2)/day without and with recirculation, respectively). Complete perchlorate reduction was sustained for influent concentrations of 400 and 10 microg/L in both flow regimes at the lower hydraulic loading rates. Reactor tracer profiles showed that biofilm diffusion had a more significant effect on mass transfer in the plug flow reactor compared with recirculation. The recirculation bioreactor acclimated more rapidly to increased hydraulic and perchlorate mass loading rates with significantly lower effluent perchlorate compared to the plug flow reactor: 16 microg/L versus 46 microg/L, respectively, although complete perchlorate removal was not achieved in either flow regime after 21 days acclimation to the higher loading. Total biofilm mass was more uniformly distributed in the recirculation reactor which may have contributed to better performance under increased perchlorate loading.     

Effect of endosulfan on growth, alpha amylase activity and plasmids amplification in Bacillus subtilis

Endosulfan, a chlorinated hydrocarbon insecticide of cyclodiene subgroup acts as a contact poison in a wide variety of organisms. In the present study, the effect of endosulfan on the growth, alpha amylase activity and plasmid amplification was investigated in Bacillus subtilis system. The bacteria were grown in medium, incubated with different concentrations (32, 48, 64 and 80 microg/mL) of endosulfan. The bacterial growth was gradually seen after 1st day at up to 48 microg/L endosulfan. The 48 microg/L endosulfan inhibited approximately 50% of the bacterial growth. No growth was observed at and after 64 microg/L endosulfan, for all days (1-5). Also, no alpha amylase activity was found in the supernatant of the culture medium containing 64 and 80 microg/L endosulfan, whereas slight activity was observed with 32 and 48 microg/L endosulfan concentration. The amount of plasmid increased up to 50% in the presence of 32 microg/L endosulfan. Endosulfan had no effect on the alpha amylase activity in vitro.     

Diazepam and propofol used as anesthetics during open-heart surgery do not cause chromosomal aberrations in peripheral blood lymphocytes

Diazepam is a benzodiazepine with anticonvulsant, anxiolytic, sedative and muscle-relaxing properties. Many aspects of its toxicity have been investigated, including genotoxic and carcinogenic effects in various model systems. However, it is still unclear whether diazepam is in fact a genotoxic agent. Propofol is a rapid-onset, short-acting intravenous anesthetic agent. It is used widely for the induction and maintenance of anesthesia as well as for long-term sedation in intensive care units. There is limited information in the literature on its genotoxic effects. Both drugs are commonly used as anesthetic in patients undergoing open-heart surgery. Therefore, we investigated the possible genotoxic effects of propofol and diazepam in those patients, using a chromosomal aberration (CA) assay. Peripheral blood samples were collected from 45 patients before induction of anesthesia and at the end of the anesthesia with diazepam or propofol. In Group I (n=24), anesthesia was induced with 0.2 mg kg(-1) diazepam and 10 microg kg(-1) fentanyl. In Group II (n=21), anesthesia was induced with 1 mg kg(-1) propofol and 10 microg kg(-1) fentanyl. Pancuronium bromide (0.1 mg kg(-1)) was administered for skeletal muscle relaxation in both groups. Anesthesia was maintained by diazepam administration at 5 mg kg(-1) in Group I or by continuous propofol administration at 2-4 mg (kg h)(-1) in Group II. All patients received 0.02 mg kg(-1) pancuronium and 5 microg kg(-1) fentanyl boluses at 30-40 min intervals for anesthesia maintenance. Body temperature was controlled during bypass in the two groups. We found that the mean frequency of CAs in both groups before and at the end of the anesthesia were not statistically significantly different. Our analysis also indicated that age, smoking habit and gender were not confounding factors. In conclusion, our results indicate that diazepam and propofol do not exert genotoxic effects in blood cells during open-heart surgery.     

Determination of urinary beryllium,arsenic, and selenium in steel production workers

Some of the most pernicious dangers of pollution arise from the presence of traces of toxic elements in the environment. In this work, we report on the determination of beryllium, arsenic, and selenium in the urine of steel production and steel quality control (QC) workers, in comparison to healthy control subjects. The urine samples were digested by a microwave system. Graphite furnace and hydride atomic absorption was used for the quantitative measurements of Be and As and Se, respectively. A quality control method for these procedures was established with concurrent analysis of Standard Trace Metals 7879 Level II and NIST SRM 2670 (Toxic Elements in Freeze Dried Urine). The results show that the urinary levels of these elements in steel production (As, 38.1±28.7 μg/L; Be, 1.58±0.46 μg/L, and Se, 69.2±28.8μg/L) and in quality control workers (As, 23.9±18.1 μg/L; Be, 1.58±0.46 μg/L, and Se, 54.8±25.1 μg/L) are significantly higher than in the controls (As, 10.3±8.7 μg/L; Be, 0.83±0.46 μg/L; and Se, 32.3±13.5 μg/L). The possible connection of these elements with the etiology of disease and the possible role of selenium as a protective agent against the oncogenic and teratogenic action of other substances is discussed. We suggest the need for improvement of environmental conditions in the workplace through better ventilation and industrial hygiene practices.     

Toxicity of the aromatase inhibitor letrozole to Japanese medaka (Oryzias latipes) eggs, larvae and breeding adults

Letrozole is a synthetic aromatase inhibitor and interferes in the committed step in the synthesis of endogenous estrogens from androgens. To evaluate potential effects on the early life stages of Japanese medaka, larvae and fertilized eggs were exposed to letrozole for 96 h and 14 days, respectively. No larvae died and no adverse effects were found on embryonic development at concentrations up to 3125 microg/L. Reproductive effects were assessed by exposing adults to 1, 5, 25, 125 and 625 microg/L letrozole for 21 days. A dose-dependent decrease in fecundity (>25 microg/L) and fertility (>5 microg/L) accompanied by histological changes suggested the inhibition of oocyte growth and possibly maturation. At 625 microg/L, the fish ceased spawning during the last week of exposure. Letrozole (>5 microg/L) reduced plasma vitellogenin levels in females in a dose-dependent manner. Transgenerational effects were evaluated by removing freshly-laid F1 eggs from letrozole-contaminated water and raising them to 15 days post-hatching in control water. Hatchability and time to hatching were detrimentally affected (>5 microg/L), but no morphological deformities were observed. Furthermore, a dose-dependent increase in the proportion of genotypic F1 males was found (>5 microg/L).     

In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L (L.) chagasi and L (Viannia) braziliensis

The leishmanicidal activity of four batches of meglumine antimoniate, produced in Farmanguinhos-Fiocruz, Brazil (TAMs), was assessed and compared to Glucantime(R)-Aventis Pharma Ltda. Using the amastigote-like in vitro model, the active concentrations of Sb v varied from 10microg/ml to 300 microg/ml for L. (L.) chagasi and from 50microg/ml to 300microg/ml for L. (L.) amazonensis, with no statistically significant differences among the four batches of TAMs and Glucantime(R). The inhibitory concentrations (IC50) determined by the amastigote-infected macrophage model for TAM01/03 and Glucantime(R) were, respectively: 26.3microg/ml and 127.6microg/ml for L. chagasi, 15.4microg /ml and 22.9microg/ml for L. amazonensis, and 12.1microg/ml and 24.2microg/ml for L. (V.) braziliensis. The activities of the four batches of TAMs were confirmed in an in vivo model by assessing, during eight weeks skin lesions caused by L. braziliensis in hamster that were treated with 20mg Sb v/Kg/day for 30 consecutive days. The meglumine antimoniate produced by Farmanguinhos was as effective as the reference drug, Glucantime(R)-Aventis, against three species of Leishmania that are of medical importance in Brazil.