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Fu S.,University of Technology, Sydney | Molnar A.,University of Technology, Sydney | Bowron P.,Toxicology Unit | Lewis J.,University of Technology, Sydney | Wang H.,Australian National Measurement Institute
Analytical and Bioanalytical Chemistry | Year: 2011

It has been previously reported that treatment of urinary oxazepam by commercial β-glucuronidase enzyme preparations, from Escherichia coli, Helix pomatia and Patella vulgata, results in production of nordiazepam (desmethyldiazepam) artefact. In this study, we report that this unusual reductive transformation also occurs in other benzodiazepines with a hydroxyl group at the C3 position such as temazepam and lorazepam. As determined by liquid chromatography-mass spectrometry analysis, all three enzyme preparations were found capable of converting urinary temazepam into diazepam following enzymatic incubation and subsequent liquid-liquid extraction procedures. For example, when H. pomatia enzymes were used with incubation conditions of 18 h and 50 °C, the percentage conversion, although small, was significant-approximately 1% (0.59-1.54%) in both patient and spiked blank urines. Similarly, using H. pomatia enzyme under these incubation conditions, a reductive transformation of urinary lorazepam into delorazepam (chlordesmethyldiazepam) occurred. These findings have both clinical and forensic implications. Detection of diazepam or delorazepam in biological samples following enzyme treatment should be interpreted with care. © 2011 Springer-Verlag. Source


Villena V.P.,Toxicology Unit
Journal of Analytical Toxicology | Year: 2010

Creatinine concentration is commonly used to verify the authenticity of urine specimens submitted for illicit drug screening. This study evaluated creatinine screening of donor urine specimens as a tool for detecting substituted and/or tampered specimens. The study carried out creatinine assay of animal urine, fruit juices, and urine from creatine-supplemented subjects by a modified version of the Jaffe reaction. All specimens were analyzed for creatinine concentration in a chemistry-immuno analyzer. Results showed that urine specimens from common domestic pets, including cats, dogs, and horses, have creatinine values similar to normal human values. Most fruit juices tested contained no detectable creatinine, and the few that did showed poor "urine" chemical integrity. Creatine supplementation by donors was found not to provide an effective means of elevating creatinine concentration in urine when attempting to flush out water-soluble drugs in the body. Thus, the assay for creatinine proved useful for the detection of some but not all adulterated urine specimens. Source


Nogue S.,University of Barcelona | Pou R.,Ramon Llull University | Fernandez J.,Toxicology Unit | Sanz-gallen P.,University of Barcelona
Occupational Medicine | Year: 2011

Fatal hydrogen sulphide poisoning usually occurs in confined spaces. We report two fatal accidents in unconfined spaces. The first accident caused the death of three workers who entered an unconfined room in a silo of sludge at the same time that a truck dumped several tons of sludge from water purification stations. The hydrogen sulphide that had accumulated inside the silo spilled out into the interior of the room due to a 'splashing effect' caused by the impact of the dumped sludge. The second accident occurred when the foreman of a wastewater treatment plant entered one of the substations to perform routine checks and suddenly lost consciousness. Although he was rapidly transferred to an intensive care unit, death occurred a few hours later. Hydrogen sulphide production was, in this case, due to an 'embolism effect' produced by the displacement of wastewater when the substation pumps were activated. We suggest ways in which accidents such as these caused by sudden release of hydrogen sulphide can be prevented. © The Author 2011. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. Source


Kong Y.W.,Toxicology Unit | Ferland-McCollough D.,Toxicology Unit | Jackson T.J.,Toxicology Unit | Jackson T.J.,University of Nottingham | Bushell M.,Toxicology Unit
The Lancet Oncology | Year: 2012

Since the identification of microRNAs (miRNAs) in 1993, and the subsequent discovery of their highly conserved nature in 2000, the amount of research into their function-particularly how they contribute to malignancy-has greatly increased. This class of small RNA molecules control gene expression and provide a previously unknown control mechanism for protein synthesis. As such, it is unsurprising that miRNAs are now known to play an essential part in malignancy, functioning as tumour suppressors and oncogenes. This Review summarises the present understanding of how miRNAs operate at the molecular level; how their dysregulation is a crucial part of tumour formation, maintenance, and metastasis; how they can be used as biomarkers for disease type and grade; and how miRNA-based treatments could be used for diverse types of malignancies. © 2012 Elsevier Ltd. Source


Gerhardt E.,University of Gottingen | Graber S.,Leibniz Institute for Molecular Pharmacology | Szego E.M.,University of Gottingen | Moisoi N.,Toxicology Unit | And 3 more authors.
PLoS ONE | Year: 2011

Heterozygous loss-of-function mutation of the human gene for the mitochondrial protease HtrA2 has been associated with increased risk to develop mitochondrial dysfunction, a process known to contribute to neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD). Knockout of HtrA2 in mice also leads to mitochondrial dysfunction and to phenotypes that resemble those found in neurodegenerative disorders and, ultimately, lead to death of animals around postnatal day 30. Here, we show that Idebenone, a synthetic antioxidant of the coenzyme Q family, and Resveratrol, a bioactive compound extracted from grapes, are both able to ameliorate this phenotype. Feeding HtrA2 knockout mice with either compound extends lifespan and delays worsening of the motor phenotype. Experiments conducted in cell culture and on brain tissue of mice revealed that each compound has a different mechanism of action. While Idebenone acts by downregulating the integrated stress response, Resveratrol acts by attenuating apoptosis at the level of Bax. These activities can account for the delay in neuronal degeneration in the striata of these mice and illustrate the potential of these compounds as effective therapeutic approaches against neurodegenerative disorders such as HD or PD. © 2011 Gerhardt et al. Source

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