William J. George

Low‐dose methylmercury‐induced oxidative stress, cytotoxicity, and tau‐hyperphosphorylation in human neuroblastoma (SH‐SY5Y) cells

Acute neurotoxic effects of high‐dose methylmercury (MeHg) in humans have been well documented in the scientific literature. However, low‐dose effects are less well described. This study was designed to evaluate the effects of low‐dose MeHg (<100 nM) on human brain cells in a tissue culture model. Neuroblastoma (NB) cells (SH‐SY5Y) were used in the cell culture model to study low‐dose effects of MeHg on cell growth, cell survival, reactive oxygen species (ROS), and the phosphorylation of tau protein, as a measure of potential markers of cellular events associated with tauopathies. When cells were incubated in culture with MeHg (50 and 100 nM), there were significant decreases in cell viability as well as significant increase in ROS generation as determined by fluorescent dye analysis (H2DCFDA). Furthermore, a concomitant decrease in glutathione levels to 25% of control was observed at both 50 and 100 nM MeHg. In addition, the level of phosphorylated tau was significantly increased after treatment at both 50 and 100 nM MeHg, compared with controls. Pretreatment of NB cells with the antioxidant, N‐acetylcysteine (1.25 mM) and the calpain inhibitor, MDL‐28170 (10 μM), significantly attenuated the effects of MeHg (50 and 100 nM) on cell viability as well as on tau phosphorylation. These results indicate that low‐dose MeHg toxicity may be related to an induction of tau phosphorylation through an oxidative stress‐dependent mechanism and that blockade of this pathway may attenuate the toxic effects of MeHg.

The Gasping Syndrome and Benzyl Alcohol Poisoning

Benzyl alcohol is commonly used as an antibacterial agent in a variety of formulations, including bacteriostatic sodium chloride and bacteriostatic water, that are intended for intravenous administ...

Pharmacokinetics and long-term tolerance to ribavirin in asymptomatic patients infected with human immunodeficiency virus.

Single‐dose and steady‐state pharmacokinetics of the antiviral agent ribavirin were studied in seven male, asymptomatic, human immunodeficiency virus‐seropositive subjects. After a single 400 mg intravenous infusion, mean terminal plasma half‐life (t½) was 27.1 hours, mean volume of distribution was 802 L, and mean total plasma clearance was 26.1 L/hr. Renal clearance was 39% of total clearance and it exceeded creatinine clearance. Oral bioavailability was 44.6%. With long‐term dosing (400 mg orally twice a day) ribavirin accumulated, reaching steady state in 2 to 4 weeks in plasma and red blood cells. Red blood cell concentrations greatly exceeded plasma concentrations (60:1). Plasma concentrations at steady state (trough) were 10‐ to 14‐fold higher than the corresponding single‐dose concentrations. The terminal t½ (washout) after 16 weeks greatly exceeded the t½ observed after a single oral dose (151 versus 29.6 hours). Ribavirin‐induced reductions in hemoglobin ranging from 0.8 to 3.5 gm/dl were well tolerated. There was no significant reduction in CD4 lymphocytes during treatment with ribavirin for 16 weeks in subjects who had more than 200 CD4 cells at entry and who also remained free of opportunistic infections during 24 weeks of observation.

Ciprofloxacin versus gentamicin in prophylaxis against bacteremia in transrectal prostate needle biopsy

Consecutive patients with abnormal rectal examinations underwent transrectal needle prostate biopsy at VA Medical Center, New Orleans. Each patient was randomized to receive either gentamicin 1.5 mg/kg intravenously (IV) or 500 mg ciprofloxacin (Cipro-Miles) p.o., before and after the biopsy. Serum and prostate tissue levels of ciprofloxacin and gentamicin were measured by high-pressure liquid chromatography and by competitive binding immunoassay, respectively. Blood cultures were obtained, and the patients were observed for twenty-four hours after biopsy. After discharge the patients were followed up by telephone. The incidence of bacteremia and postbiopsy symptoms were less with ciprofloxacin. Prostate tissue levels of this drug were higher than gentamicin, while serum levels were roughly equivalent. Ciprofloxacin is less nephrotoxic, can be given orally, and has a better antimicrobial spectrum. We, therefore, recommend it as prophylaxis against bacteremia in transrectal prostate needle biopsy. Furthermore, it appears that prostatic drug levels are more important than serum levels in preventing bacteremia.

Effects of acute and chronic exposure to cobalt on male reproduction in mice

Chronic exposure of male mice to cobaltous chloride dramatically affected their reproductive potential, while acute administration had minimal effects. Acute exposure, followed by evaluation weekly over a 7-week period, revealed no significant changes in epididymal sperm concentration or testicular weight. However, small but significant decreases in fertility at weeks 2 and 3 of the study were observed. Sperm motility was depressed only during the first week of the study. In chronic studies, cobalt affected fertility in a time- and dose-dependent manner. There was a decrease in testicular weight, epididymal sperm concentration, and fertility. Sperm motility was also depressed. Serum testosterone levels were dramatically increased in cobalt treated animals, while FSH and LH serum levels were normal. It appears that cobalt is directly or indirectly interfering with spermatogenesis and with local regulatory mechanisms in testosterone synthesis.

Bioaccumulation of lead nitrate in red swamp crayfish (Procambarus clarkii)

Abstract Crayfish were exposed to intermediate concentrations of lead nitrate (150 μgl −1 and 1100 μgl −1 ) for periods up to 7 weeks. Lead clearance was monitored at 3 weeks following the 7 week exposure to the lower concentration. Lead bioaccumulation was demonstrated to be a time- and dose-dependent phenomenon in gills, hepatopancreas and abdominal muscle, but not the exoskeleton. The tissue concentrations of lead in soft tissues, in decreasing order were gills > hepatopancreas > muscle > hemolymph. Lead clearance was significant in all tissues evaluated except the hepatopancreas, the organ of metal storage and detoxification.

High-pressure liquid chromatography/electrochemical detection method for monitoring MDA and MDMA in whole blood and other biological tissues

The drug Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) is one of several hallucinogenic amphetamine derivatives reported to be serotonergic neurotoxins. The following is a description of a new high-pressure liquid chromatographic (HPLC) analytical method for the analysis of MDMA, 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDE) from whole blood. Upon separation of MDMA, MDA and MDE by HPLC, quantitation is achieved by use of electrochemical detection. Retention times for MDA, MDMA, and MDE are 6.5, 9.2, and 10.3 min, respectively, allowing for a complete chromatographic run every 15 min. The sensitivity of the method is 1 ng/ml which allows for measurement of MDA, MDMA, or MDE in microsamples of whole blood. The volume of blood required is very small (200 microliters); therefore, there is minimal blood loss in repeated blood sampling from small animals. Assay linearity was demonstrated from 1 ng/ml to at least 1 microgram/ml. The coefficients of variation for both intra-assay and inter-assay comparisons were less than 9%. Other HPLC methods have been previously described for the analysis of amphetamine derivatives, but this new method offers greater sensitivity, rapid turn-around time and ease of use.

Ambient particulate matter, C-reactive protein, and coronary artery disease

Abstract This article is a review of the scientific literature with respect to fine particulate matter (PM), 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and coronary artery disease (CAD). The association between air pollution and respiratory diseases has been extensively investigated for decades; however, the role of air pollution in exacerbating heart disease has only recently become a focus of attention. It has been shown that for every 10-μg/m3 increase in fine PM in the air, there appears to be a 2.1% increase in the number of deaths related to ischemic heart disease. PM has been linked to increased levels of systemic inflammation biomarkers such as C-reactive proteins (CRP). Daily variation of ambient pollution is correlated with rises and falls in CRP levels. Increased CRP levels have been associated with increased morbidity and mortality in individuals with CAD. Seventy-five percent of patients with elevated CRP levels have reportedly experienced a major cardiac event despite low-density lipoproteins (LDL) levels that were below the threshold recommended for pharmacological intervention. HMG CoA reductase inhibitors (statins) have been shown to cause a reduction in coronary events by lowering LDL levels. However, recently it has been shown that statins have the effect of lowering CRP levels. This may explain why individuals with normal lipid levels may benefit from statin therapy. Ambient PM exposure levels and its effects on CRP are risk factors associated with coronary events and should be considered as a target for the treatment of CAD.

Bioaccumulation of chromium in red swamp crayfish (Procambarus clarkii)

Abstract Crayfish were exposed to a range of potassium dichromate concentrations (0.15, 0.30, 3.0 and 30 mg l−1) for periods up to 7 weeks. Chromium bioaccumulation in all tissues over the 7 week exposure period was not consistently time- and dose-dependent. The order of distribution of chromium into the various tissues was dependent upon the exposure concentration of the metal. Chromium clearance studies conducted 1 and 3 weeks following exposure demonstrated a concentration reduction in most tissues only at the highest exposure concentration of chromium (30 mg l−1). Histological studies demonstrated damage to both the gills and hepatopancreas at the lowest exposure concentration. The results suggest that the red swamp crayfish, Procambarus clarkii, is a useful biomarker for chromium exposure.

Urinary excretion of 6‐hydroxychlorzoxazone as an index of CYP2E1 activity

To determine whether the urinary excretion of 6‐hydroxychlorzoxazone is an index of CYP2E1 activity in vivo.