Toxicology Unit

Cáceres, Spain

Toxicology Unit

Cáceres, Spain

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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.

Marino A.,University of Rome Tor Vergata | Menghini R.,University of Rome Tor Vergata | Fabrizi M.,University of Rome Tor Vergata | Casagrande V.,University of Rome Tor Vergata | And 12 more authors.
Diabetes | Year: 2014

Classically activated macrophages (M1) secrete proinflammatory cytokine and are predominant in obese adipose tissue. M2 macrophages, prevalent in lean adipose tissue, are induced by IL-13 and IL-4, mainly secreted by Th2 lymphocytes, and produce the anti-inflammatory cytokine IL-10. ITCH is a ubiquitously expressed E3 ubiquitin ligase involved in T-cell differentiation and in a wide range of inflammatory pathways. ITCH downregulation in lymphocytes causes aberrant Th2 differentiation. To investigate the role of Th2/M2 polarization in obesityrelated inflammation and insulin resistance, we compared wild-type and Itch2/2 mice in a context of diet-induced obesity (high-fat diet [HFD]). When subjected to HFD, Itch2/2 mice did not show an increase in body weight or insulin resistance; calorimetric analysis suggested an accelerated metabolism. The molecular analysis of metabolically active tissue revealed increased levels of M2 markers and genes involved in fatty acid oxidation. Histological examination of livers from Itch2/2 mice suggested that ITCH deficiency protects mice from obesity-related nonalcoholic fatty liver disease. We also found a negative correlation between ITCH and M2 marker expression in human adipose tissues. Taken together, our data indicate that ITCH E3 ubiquitin ligase deficiency protects from the metabolic disorder caused by obesity. © 2014 by the American Diabetes Association.

Glinn M.,Toxicology Unit | Adatsi F.,Toxicology Unit | Curtis P.,Alcohol Enforcement Unit
Journal of Forensic Sciences | Year: 2011

The State of Michigan uses the Datamaster as an evidential breath testing device. The newest version, the DMT, will replace current instruments in the field as they are retired from service. The Michigan State Police conducted comparison studies to test the analytical properties of the new instrument and to evaluate its response to conditions commonly cited in court defenses. The effects of mouth alcohol, objects in the mouth, and radiofrequency interference on paired samples from drinking subjects were assessed on the DMT. The effects of sample duration and chemical interferents were assessed on both instruments, using drinking subjects and wet-bath simulators, respectively. Our testing shows that Datamaster and DMT results are essentially identical; the DMT gave accurate readings as compared with measurements made using simulators containing standard ethanol solutions and that the DMT did not give falsely elevated breath alcohol results from any of the influences tested. © 2011 American Academy of Forensic Sciences.

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.

Wilhelm M.T.,Princess Margaret Hospital | Wilhelm M.T.,Karolinska Institutet | Rufini A.,Princess Margaret Hospital | Rufini A.,Toxicology Unit | And 16 more authors.
Genes and Development | Year: 2010

Mice with a complete deficiency of p73 have severe neurological and immunological defects due to the absence of all TAp73 and ΔNp73 isoforms. As part of our ongoing program to distinguish the biological functions of these isoforms, we generated mice that are selectively deficient for the ΔNp73 isoform. Mice lacking ΔNp73 (ΔNp73-/- mice) are viable and fertile but display signs of neurodegeneration. Cells from ΔNp73 -/- mice are sensitized to DNA-damaging agents and show an increase in p53-dependent apoptosis. When analyzing the DNA damage response (DDR) in ΔNp73-/- cells, we discovered a completely new role for ΔNp73 in inhibiting the molecular signal emanating from a DNA break to the DDR pathway. We found that ΔNp73 localizes directly to the site of DNA damage, can interact with the DNA damage sensor protein 53BP1, and inhibits ATM activation and subsequent p53 phosphorylation. This novel finding may explain why human tumors with high levels of ΔNp73 expression show enhanced resistance to chemotherapy. © 2010 by Cold Spring Harbor Laboratory Press.

Couchman L.,Toxicology Unit | Birch M.,Toxicology Unit | Ireland R.,King's College | Corrigan A.,St Thomas Hospital | And 4 more authors.
Analytical and Bioanalytical Chemistry | Year: 2012

Tyrosine kinase inhibitors (TKIs) are used to treat a number of cancers, including chronic myeloid leukaemia and hepatocellular carcinoma. Therapeutic drug monitoring (TDM) may be indicated to (1) monitor adherence, (2) guide dosage, and (3) minimise the risk of drug-drug interactions and dose-related toxicity. On-line, automated sample preparation provided by TurboFlow technology (ThermoFisher Scientific) in conjunction with the sensitivity and selectivity of tandem mass spectrometry (MS/MS) detection may be applied to the analysis of single drugs and metabolites. We report the use of TurboFlow LC-MS/MS for the analysis of nine TKIs and metabolites (imatinib, N-desmethylimatinib, dasatinib, nilotinib, erlotinib, gefitinib, lapatinib, sorafenib, sunitinib) in human plasma or serum for TDM purposes. An Aria Transcend TLX-II system coupled with a TSQ Vantage was used. Samples (50 μL) were vortex mixed with internal standard solution (150 μL imatinib-D8, gefitinib-D8, sunitinib-D 10, and nilotinib- 13C 2 15N2 in acetonitrile) and, after centrifugation 100 μL supernatant were injected directly onto a 50×0.5-mm Cyclone TurboFlow column. Analytes were focussed onto a 50×2.1-mm (3 μm) Hypersil GOLD analytical column and eluted with an acetonitrile/ water gradient. Analytes were monitored in selected reaction monitoring mode (positive APCI). Total analysis time was 7 min without multiplexing. Calibration was linear (R2>0.99) for all analytes. Inter- and intra-Assay precision (in percent relative standard deviation, RSD) was <11 % and accuracy 89-117 % for all analytes. No matrix effects were observed. This method is suitable for high-Throughput TDM in patients undergoing chronic therapy with TKIs and has been utilised in the analysis of clinical samples. © Springer-Verlag 2012.

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.

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.

Ensibi C.,University of Carthage | Perez-Lopez M.,Toxicology Unit | Soler Rodriguez F.,Toxicology Unit | Miguez-Santiyan M.P.,Toxicology Unit | And 2 more authors.
Environmental Toxicology and Pharmacology | Year: 2013

The present study is aimed to evaluate the effect of sublethal exposure to the pyrethroid pesticide deltamethrin, according to biometric parameters and important liver biomarkers in the common carp (Cyprinus carpio). Fish were exposed for 4, 15 and 30 days to deltamethrin mixed to the aquaria water at the concentrations of 0.08, 0.4 and 0.8. μg/L. The exposure did not affect fish biometric parameters. Glutathione-S-transferase (GST) activity in liver (hepatopancreas) increased in fish exposed to the high concentration of pesticide only after 30 days when compared to controls. A significant increase of malondialdehyde (MDA) content (79.4% and 90.2% of control) was remarked after 15 and 30 days of exposure to the highest concentration of pesticide. Catalase activities (CAT) went up after 4 days of was to the concentration of 0.4. μg/L and 0.8. μg/L and at 15 days of exposure to 0.4. μg/L. The most significant change of glutathione reductase (GR) activity was recorded at the fourth day, when GR activity was significantly increased after exposure to the concentrations of 0.4. μg/L and 0.8. μg/L of deltamethrin. © 2013 Elsevier B.V.

Ensibi C.,University of Carthage | Hernandez-Moreno D.,Toxicology Unit | Miguez Santiyan M.P.,Toxicology Unit | Daly Yahya M.N.,University of Carthage | And 2 more authors.
Environmental Toxicology | Year: 2014

This work investigated the effect from exposure to insecticides carbofuran and deltamethrin on acetylcholinesterase (AChE) activity in the brain and muscle of common carp (Cyprinus carpio). Both pesticides were evaluated through two separate experiments, and carp were exposed in a semi-static system to three different concentrations of carbofuran (10, 50, and 100 μg/L) and deltamethrin (0.08, 0.4, and 0.8 μg/L) during a month with sampling times at 0, 4, 15, and 30 days (n = 7 from each aquarium). AChE activity was significantly inhibited in both organs of carps exposed to carbofuran at all sampling times depending on dose and time, reaching inhibition values of 73.5 and 67.1%, in brain and muscle tissues respectively, after 30 days with the highest concentration. On the contrary, AChE activity was not significantly affected after deltamethrin exposure at all concentrations and times of the assay. This study shows that the measurement of brain and muscle AChE activity in Cyprinus carpio is a useful biomarker of carbamates exposure and/or effects, but has no application with pyrethroids. © 2012 Wiley Periodicals, Inc.

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