A hematology surveillance study of petrochemical workers exposed to 1,3 butadiene

Complete blood counts (CBC) have been recognized as an easy and readily available screen for hematotoxicity following occupational exposure to 1,3-butadiene. This study evaluated hematology data from employees who have ever participated in the Shell Butadiene Medical Surveillance Program (BMSP), compared with employees who have not participated. This study examined potential hematopoietic toxicity in relation to the occupational exposures at two Shell facilities. This study included 404 employees who participated in the BMSP, with mean butadiene exposure (TWA-8, TWA-10, and TWA-12 together) of 4.55 ppm from 1979-1996 and 0.25 ppm from 1997-2003, and 773 comparison employees. The comparison group included employees not participating in either the benzene or butadiene surveillance programs. Abnormality of six CBC parameters, including white blood cell count, red blood cell count, lymphocyte count, hemoglobin concentration, mean corpuscular volume and platelet count, and the adjusted mean values of these parameters in the exposed group were compared with those of the comparison group. We found no significantly increased abnormality for any hematology parameter among exposed employees. The adjusted mean values (adjusted for age, sex, race, length of time between first and last exam, current smoking status, and first exam value) of the exposed employees were similar to those in the comparison group. At current occupational exposure levels for 1,3-butadiene, there is no evidence of adverse hematological effects observed in this study. These findings are consistent with results of three similar studies in the literature.     

In vivo microstructural analysis of the cornea in Maroteaux-Lamy syndrome

PURPOSE: This report describes the clinical and in vivo microstructural features of the cornea in a case of Maroteaux-Lamy syndrome. METHODS: A 17-year-old female with Maroteaux-Lamy syndrome was examined by slit-lamp biomicroscopy, Orbscan II slit-scanning elevation topography, and in vivo confocal microscopy. RESULTS: Slit-lamp biomicroscopy revealed bilateral, altered corneal transparency involving the posterior half of the stroma. Funduscopy revealed bilateral small, crowded optic discs, and radial macula retinal folds.On in vivo confocal microscopy, the middle and posterior stroma were clearly visualized and exhibited well-defined, unusually shaped keratocytes. These cells contained single or multiple hyporeflective regions with well-defined borders that ranged from 1 to 11.6 microm in diameter. These abnormal keratocytes were particularly abundant in the posterior stroma and sparse in the anterior stroma. CONCLUSIONS: This is the first case of Maroteaux-Lamy syndrome in which altered corneal transparency has been imaged by in vivo confocal microscopy and macula retinal folds have been described.     

Meta-analysis of natural therapies for hyperlipidemia: plant sterols and stanols versus policosanol

STUDY OBJECTIVE: To compare the efficacy and safety of plant sterols and stanols as well as policosanol in the treatment of coronary heart disease, as measured by a reduction in low-density lipoprotein cholesterol (LDL) levels. DESIGN: Systematic review and meta-analysis of randomized controlled trials. PATIENTS: A total of 4596 patients from 52 eligible studies. MEASUREMENTS AND MAIN RESULTS: We searched MEDLINE, EMBASE, the Web of Science, and the Cochrane Library from January 1967-June 2003 to identify pertinent studies. Reduction of LDL levels was the primary end point; effects on other lipid parameters and withdrawal of study patients due to adverse effects were the secondary end points. Weighted estimates of percent change in LDL were -11.0% for plant sterol and stanol esters 3.4 g/day (range 2-9 g/day [893 patients]) versus -2.3% for placebo (769 patients) in 23 eligible studies, compared with -23.7% for policosanol 12 mg/day (range 5-40 mg/day [1528 patients]) versus -0.11% for placebo (1406 patients) in 29 eligible studies. Cumulative p values were significantly different from placebo for both (p<0.0001). The net LDL reduction in the treatment groups minus that in the placebo groups was greater with policosanol than plant sterols and stanols (-24% versus -10%, p<0.0001). Policosanol also affected total cholesterol, high-density lipoprotein cholesterol (HDL), and triglyceride levels more favorably than plant sterols and stanols. Policosanol caused a clinically significant decrease in the LDL:HDL ratio. Pooled withdrawal rate due to adverse effects and combined relative risk for patients who withdrew were 0% and 0.84, respectively (95% confidence interval [CI] 0.36-1.95, p=0.69), for plant sterols and stanols across 20 studies versus 0.86% and 0.31, respectively (95% CI 0.20-0.48, p<0.0001), for policosanol across 28 studies. CONCLUSION: Plant sterols and stanols and policosanol are well tolerated and safe; however, policosanol is more effective than plant sterols and stanols for LDL level reduction and more favorably alters the lipid profile, approaching antilipemic drug efficacy.     

Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4'-fluoro substitution prevents quinoid formation

Although selective estrogen receptor modulators (SERMs) are useful in the treatment and prevention of breast cancer, the SERM tamoxifen has been associated with an increased risk of endometrial cancer possibly due to metabolism to electrophilic quinoids. Another SERM, arzoxifene is currently in clinical trials for the treatment of breast cancer, and since it has similar structural characteristics to tamoxifen, it also has the potential to form quinoids. In the current study, the active form of arzoxifene in vivo, desmethylated arzoxifene (DMA), was synthesized and chemically or enzymatically oxidized to DMA diquinone methide. The half-life of DMA diquinone methide at physiological pH and temperature was approximately 15 s. Reaction of DMA diquinone methide with glutathione (GSH) gave four mono-GSH conjugates, two di-GSH conjugates, and one tri-GSH conjugate. In incubations of DMA with GSH and either rat or human liver microsomes, DMA o-quinone-GSH conjugates were detected in addition to DMA diquinone methide-GSH conjugates. A DMA diquinone methide-deoxyguanosine adduct was detected following the incubation of DMA diquinone methide with deoxynucleosides. In preliminary studies with a human breast cancer cell line, DMA induced dose-dependent DNA damage and was more effective at causing DNA damage than raloxifene. These results suggest that DMA can be metabolized to electrophilic/redox-active quinoids, which have the potential to cause toxicity in vivo. A new fluorinated derivative unable to form a diquinone methide, 4'-F-DMA, was synthesized. 4'-F-DMA showed similar estrogen receptor (ER) binding affinity as compared to DMA. The antiestrogenic activity as measured by inhibition of estradiol-mediated induction of alkaline phosphatase activity in Ishikawa cells showed 10-fold lower activity for 4'-F-DMA compared to DMA; however, the antiestrogenic activity was comparable to raloxifene. In microsomal incubations of 4'-F-DMA in the presence of GSH, no GSH adducts were detected. These data suggest that 4'-F-DMA might be a promising SERM with similar activity to DMA and raloxifene and less toxicity.     

Colchicine decreases airway hyperreactivity after phosgene exposure

Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses that (1) phosgene exposure increases airway reactivity and (2) colchicine can decrease this elevation. Sprague Dawley rats (70 d old; male) were exposed to 1 ppm COCl(2) for 1 h. Airway reactivity was tested at 0, 4, and 24 h postexposure by infusing anesthetized animals intravenously with acetylcholine and assessing expiratory resistance and dynamic compliance. Immediately and 4 h postexposure, a significant change in expiratory resistance and dynamic compliance was observed in those animals exposed to COCl(2), while at 24 h this response was greater. A second experiment was performed in rats pretreated with colchicine (1 mg/kg) or saline given intraperitoneally, exposed to 1 ppm COCl(2) for 1 h, with both expiratory resistance and dynamic compliance assessed at 24 h. After exposure, cell differentials and protein in lavage were also quantitated. The results indicate that colchicine decreased neutrophil influx, protein accumulation, and changes in both expiratory resistance and dynamic compliance after COCl(2) exposure. Colchicine may affect injury and changes in expiratory resistance and dynamic compliance by diminishing the incursion of inflammatory cells, but other properties of this medication may also be responsible for the observed results.     

Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by Pseudomonas aeruginosa ExoY

Mammalian transmembrane adenylyl cyclases synthesize a restricted plasmalemmal cAMP pool that is intensely endothelial barrier protective. Bacteria have devised mechanisms of transferring eukaryotic factor-dependent adenylyl cyclases into mammalian cells. Pseudomonas aeruginosa ExoY is one such enzyme that catalyzes cytosolic cAMP synthesis, with unknown function. Pseudomonas aeruginosa genetically modified to introduce only the ExoY toxin elevated cAMP 800-fold in pulmonary microvascular endothelial cells over 4 hours, whereas a catalytically deficient (ExoY(K81M)) strain did not increase cAMP. ExoY-derived cAMP was localized to a cytosolic microdomain not regulated by phosphodiesterase activity. In contrast to the barrier-enhancing actions of plasmalemmal cAMP, the ExoY cytosolic cAMP pool induced endothelial gap formation and increased the filtration coefficient in the isolated perfused lung. These findings collectively illustrate a previously unrecognized mechanism of hyperpermeability induced by rises in cytosolic cAMP.