RNOP-09: pegylated liposomal doxorubicine and prolonged temozolomide in addition to radiotherapy in newly diagnosed glioblastoma--a phase II study.

BACKGROUND: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for. METHODS: In this phase-I/II trial, pegylated liposomal doxorubicin (Caelyx, PEG-Dox) and prolonged administration of Temozolomide in addition to radiotherapy was investigated in 63 patients with newly diagnosed glioblastoma. In phase-I, PEG-Dox was administered in a 3-by-3 dose-escalation regimen. In phase-II, 20 mg/m2 PEG-Dox was given once prior to radiotherapy and on days 1 and 15 of each 28-day cycle starting 4 weeks after radiotherapy. Temozolomide was given in a dose of 75 mg/m2 daily during radiotherapy (60 Gy) and 150-200 mg/m2 on days 1-5 of each 28-day cycle for 12 cycles or until disease progression. RESULTS: The toxicity of the combination of PEG-Dox, prolonged administration of Temozolomide, and radiotherapy was tolerable. The progression free survival after 12 months (PFS-12) was 30.2%, the median overall survival was 17.6 months in all patients including the ones from Phase-I. None of the endpoints differed significantly from the EORTC26981/NCIC-CE.3 data in a post-hoc statistical comparison. CONCLUSION: Together, the investigated combination is tolerable and feasible. Neither the addition of PEG-Dox nor the prolonged administration of Temozolomide resulted in a meaningful improvement of the patient's outcome as compared to the EORTC26981/NCIC-CE.3 data.

Fatal metformin overdose: case report and postmortem biochemistry contribution.

Metformin is an oral antihyperglycemic agent used in the management of type 2 diabetes mellitus. Lactic acidosis from metformin overdose is a rare complication of metformin therapy and occurs infrequently with therapeutic use. Fatal cases, both accidental and intentional, are extremely rare in clinical practice. Metformin is eliminated by the kidneys, and impaired renal function can result in an increased plasma concentration of the drug. In this report, we describe an autopsy case involving a 70-year-old woman suffering from diabetes mellitus and impaired renal function who received metformin treatment. Metformin concentrations in the peripheral blood collected during hospitalization and femoral blood collected during autopsy were 42 and 47.3 µg/ml, respectively. Lactic acidosis (29.10 mmol/l) was objectified during hospitalization. Furthermore, postmortem biochemistry allowed ketoacidosis to be diagnosed (blood β-hydroxybutyrate, 10,500 µmol/l). Death was attributed to lactic acidosis due to metformin intoxication. Increased plasma concentrations of the drug were attributed to severely impaired renal function. The case emphasizes the usefulness of performing exhaustive toxicology and postmortem biochemistry towards the more complete understanding of the pathophysiological mechanisms that may be involved in the death process.

Development of a control banding tool for nanomaterials

Control banding (CB) can be a useful tool for managing the potential risks of nanomaterials. The here proposed CB, which should be part of an overall risk control strategy, groups materials by hazard and emission potential. The resulting decision matrix proposes control bands adapted to the risk potential levels and helps define an action plan. If this plan is not practical and financially feasible, a full risk assessment is launched. The hazard banding combines key concepts of nanomaterial toxicology: translocation across biological barriers, fibrous nature, solubility, and reactivity. Already existing classifications specific to the nanomaterial can be used "as is." Otherwise, the toxicity of bulk or analogous substances gives an initial hazard band, which is increased if the substance is not easily soluble or if it has a higher reactivity than the substance. The emission potential bands are defined by the nanomaterials' physical form and process characteristics. Quantities, frequencies, and existing control measures are taken into account during the definition of the action plan. Control strategies range from room ventilation to full containment with expert advice. This CB approach, once validated, can be easily embedded in risk management systems. It allows integrating new toxicity data and needs no exposure data. [Authors]

Lead acetate toxicity in vitro: Dependence on the cell composition of the cultures.

It is well known that exposure to low doses of lead causes long-lasting neurobehavioural deficits, but the cellular changes underlying these behavioural changes remain to be elucidated. A protective role of glial cells on neurons through lead sequestration by astrocytes has been proposed. The possible modulation of lead neurotoxicity by neuron-glia interactions was examined in three-dimensional cultures of foetal rat telencephalon. Mixed-brain cell cultures or cultures enriched in either neurons or glial cells were treated for 10 days with lead acetate (10(-6) m), a concentration below the limit of cytotoxicity. Intracellular lead content and cell type-specific enzyme activities were determined. It was found that in enriched cultures neurons stored more lead than glial cells, and each cell type alone stored more lead than in co-culture. Moreover, glial cells but not neurons were more affected by lead in enriched culture than in co-culture. These results show that neuron-glia interactions attenuate the cellular lead uptake and the glial susceptibility to lead, but they do not support the idea of a protective role of astrocytes.

'Toxic' and 'Nontoxic': confirming critical terminology concepts and context for clear communication

If 'the dose makes the poison', and if the context of an exposure to a hazard shapes the risk as much as the innate character of the hazard itself, then what is 'toxic' and what is 'nontoxic'? This article is intended to help readers and communicators: anticipate that concepts such as 'toxic' and 'nontoxic' may have different meanings to different stakeholders in different contexts of general use, commerce, science, and the law; recognize specific situations in which terms and related information could potentially be misperceived or misinterpreted; evaluate the relevance, reliability, and other attributes of information for a given situation; control actions, assumptions, interpretations, conclusions, and decisions to avoid flaws and achieve a desired outcome; and confirm that the desired outcome has been achieved. To meet those objectives, we provide some examples of differing toxicology terminology concepts and contexts; a comprehensive decision-making framework for understanding and managing risk; along with a communication and education message and audience-planning matrix to support the involvement of all relevant stakeholders; a set of CLEAR-communication assessment criteria for use by both readers and communicators; example flaws in decision-making; a suite of three tools to assign relevance vs reliability, align know vs show, and refine perception vs reality aspects of information; and four steps to foster effective community involvement and support. The framework and supporting process are generally applicable to meeting any objective.

Hydrogen sulfide measurement by headspace-gas chromatography-mass spectrometry (HS-GC-MS): application to gaseous samples and gas dissolved in muscle.

The aim of our study was to present a new headspace-gas chromatography-mass spectrometry (HS-GC-MS) method applicable to the routine determination of hydrogen sulfide (H(2)S) concentrations in biological and gaseous samples. The primary analytical drawback of the GC/MS methods for H(2)S measurement discussed in the literature was the absence of a specific H(2)S internal standard required to perform quantification. Although a deuterated hydrogen sulfide (D(2)S) standard is currently available, this standard is not often used because this standard is expensive and is only available in the gas phase. As an alternative approach, D(2)S can be generated in situ by reacting deuterated chloride with sodium sulfide; however, this technique can lead to low recovery yield and potential isotopic fractionation. Therefore, N(2)O was chosen for use as an internal standard. This method allows precise measurements of H(2)S concentrations in biological and gaseous samples. Therefore, a full validation using accuracy profile based on the β-expectation tolerance interval is presented. Finally, this method was applied to quantify H(2)S in an actual case of H(2)S fatal intoxication.

Aggregat-Zellkulturen

Aggregate cultures are primary cell cultures prepared from dissociated fetal cells. In rotation-mediated culture under rigorously controlled conditions, the isolated cells are able to reaggregate spontaneously, and to form a large number of practically identical spheres. The three-dimensional cell structure in each aggregate provides a maximum of cell-cell interactions, and thus enables the cells to rearrange and to develop in an organotypic fashion. Relatively simple techniques are now available which permit the preparation of aggregate cultures from fetal brain and liver cells. Since they can be grown in a chemically defined medium, and because they mimic several morphogenetic events occurring in vivo, these cultures offer a unique model for developmental studies. Moreover, they may be used as well for routine testing, for example for screening purposes in toxicology, and thus contribute to the reduction of animal experiments.

FLIP prevents apoptosis induced by death receptors but not by perforin/granzyme B, chemotherapeutic drugs, and gamma irradiation.

FLICE-inhibitory protein, FLIP (Casper/I-FLICE/FLAME-1/CASH/CLARP/MRIT), which contains two death effector domains and an inactive caspase domain, binds to FADD and caspase-8, and thereby inhibits death receptor-mediated apoptosis. Here, we characterize the inhibitory effect of FLIP on a variety of apoptotic pathways. Human Jurkat T cells undergoing Fas ligand-mediated apoptosis in response to CD3 activation were completely resistant when transfected with FLIP. In contrast, the presence of FLIP did not affect apoptosis induced by granzyme B in combination with adenovirus or perforin. Moreover, the Fas ligand, but not the perforin/granzyme B-dependent lytic pathway of CTL, was inhibited by FLIP. Apoptosis mediated by chemotherapeutic drugs (i.e., doxorubicin, etoposide, and vincristine) and gamma irradiation was not affected by FLIP or the absence of Fas, indicating that these treatments can induce cell death in a Fas-independent and FLIP-insensitive manner.

Intoxications létales à l'amisulpride en Suisse romande depuis 2005 : concentrations sanguines thérapeutiques, toxiques et létales. [Lethal amisulpride intoxications in Western Switzerland since 2005: Therapeutical, toxic and lethal concentrations]

Parmi les neuroleptiques disponibles, l'amisulpride est de plus en plus prescrit. De par son affinité sélective dose-dépendante aux récepteurs dopaminergiques, il est possible de moduler les effets de cette substance montrant des propriétés antidépressives à faible dose et agissant comme un puissant antipsychotique à forte dose. Toutefois, l'amisulpride induit une prolongation dose-dépendante de l'intervalle QT ce qui peut potentialiser la survenue d'arythmies ventriculaires, souvent fatales lorsque sa consommation est concomitante à celles d'autres médicaments ou stupéfiants allongeant l'intervalle QT. Cependant, la littérature scientifique demeure peu documentée en ce qui concerne la détermination de concentrations sanguines thérapeutiques, toxiques et létales. Après avoir présenté les propriétés pharmacodynamiques et pharmacocinétiques de l'amisulpride, nous nous proposons de définir plus précisément les seuils sanguins de concentrations thérapeutiques, toxiques et létales pour cette molécule illustrée par la revue des cas mortels impliquant l'amisulpride en Suisse romande depuis 2005. Among the available neuroleptic drugs, amisulpride is increasingly prescribed. Thanks to its dose-dependent selective affinity for dopamine receptors, it is possible to modulate the effects of this substance showing antidepressant properties at low dose and acting as a powerful antipsychotic at high dose. However, amisulpride induces a dose-dependent prolongation of the QT interval which may potentiate the occurrence of ventricular arrhythmias, often fatal when its consumption is concomitant with those of other drugs that prolong the QT interval. However, the scientific literature remains poorly documented with regard to the determination of therapeutic, toxic and lethal blood concentrations. After presenting the pharmacodynamic and pharmacokinetic properties of amisulpride, we propose to define more precisely the blood levels of therapeutic, toxic and lethal concentrations for this molecule illustrated by a review of the fatal cases involving amisulpride in Western Switzerland since 2005.

Management of nanomaterials safety in research environment

Despite numerous discussions, workshops, reviews and reports about responsible development of nanotechnology, information describing health and environmental risk of engineered nanoparticles or nanomaterials is severely lacking and thus insufficient for completing rigorous risk assessment on their use. However, since preliminary scientific evaluations indicate that there are reasonable suspicions that activities involving nanomaterials might have damaging effects on human health; the precautionary principle must be applied. Public and private institutions as well as industries have the duty to adopt preventive and protective measures proportionate to the risk intensity and the desired level of protection. In this work, we present a practical, 'user-friendly' procedure for a university-wide safety and health management of nanomaterials, developed as a multi-stakeholder effort (government, accident insurance, researchers and experts for occupational safety and health). The process starts using a schematic decision tree that allows classifying the nano laboratory into three hazard classes similar to a control banding approach (from Nano 3 - highest hazard to Nano1 - lowest hazard). Classifying laboratories into risk classes would require considering actual or potential exposure to the nanomaterial as well as statistical data on health effects of exposure. Due to the fact that these data (as well as exposure limits for each individual material) are not available, risk classes could not be determined. For each hazard level we then provide a list of required risk mitigation measures (technical, organizational and personal). The target 'users' of this safety and health methodology are researchers and safety officers. They can rapidly access the precautionary hazard class of their activities and the corresponding adequate safety and health measures. We succeed in convincing scientist dealing with nano-activities that adequate safety measures and management are promoting innovation and discoveries by ensuring them a safe environment even in the case of very novel products. The proposed measures are not considered as constraints but as a support to their research. This methodology is being implemented at the Ecole Polytechnique de Lausanne in over 100 research labs dealing with nanomaterials. It is our opinion that it would be useful to other research and academia institutions as well. [Authors]

Ethyl glucuronide in plant extracts :O16

Introduction: The specificity of ethyl glucuronide (EtG) in hair as marker of alcohol consumption exceeds by far those of fatty acid ethyl esters. False positive cases are therefore very rare but not excluded as recent publications have shown. Especially, the use of plant extracts containing high percentages of ethanol can lead to EtG hair concentrations typically found in cases of chronic alcohol consumption. As proposed by Baumgartner et al., a nucleohilic substitution could most likely explain this phenomenon. Fresh and dried plants as well as commercial hair lotions based on plants extracts have been analysed for EtG presence or EtG formation. Methods: Urtica dioica, Plantago lanceolata, Cortex Quercus, Sempervivum, Armoracia rusticana, Juniperus communis, Brassica alba, Thymian vulgaris, Salvia officinalis, Majorana hortensis, Aloe vera, birch gingko and green tea leafs, ginger, lemon grass were extracted in water, water/ethanol (50/50) and ethanol (100%). The extracts as well as diluted hair lotions were measured by immunological test (Microgenics DRI® EtG assay) and by LC-MS/MS on Shimadzu Nexera UHPLC coupled with an AB Sciex 4500 QTrap. Results: EtG could not be detected in water extracts of all tested plants. However, DRI® EtG assay indicated the presence of EtG in 66% of the tested ethanolic plant extracts. That could only be confirmed by mass spectrometry in the cases of fresh thyme as well as in dried birch, oak and plantain extracts where EtG concentrations between of 0.25 and 2,09 mg/l were measured. In one hair lotion, the EtG concentration was 0,76 mg/l. Conclusion: Ethanolic plant extracts represents a non-negligible risk for false positive EtG hair tests, especially when applied as lotion without following washing out. The use of hair care products must therefore be evaluated at every hair sampling. In case of doubt, the product should be analysed by mass spectrometric methods since the presence of EtG can't be proven by use of the DRI® EtG assay, only. Our results support Baumgartner's assumption of a nucleophilic substitution in presence of ethanol because EtG was only measured in the ethanolic extracts.

Stress reaction of kidney epithelial cells to inorganic solid-core nanoparticles.

A route of accumulation and elimination of therapeutic engineered nanoparticles (NPs) may be the kidney. Therefore, the interactions of different solid-core inorganic NPs (titanium-, silica-, and iron oxide-based NPs) were studied in vitro with the MDCK and LLC-PK epithelial cells as representative cells of the renal epithelia. Following cell exposure to the NPs, observations include cytotoxicity for oleic acid-coated iron oxide NPs, the production of reactive oxygen species for titanium dioxide NPs, and cell depletion of thiols for uncoated iron oxide NPs, whereas for silica NPs an apparent rapid and short-lived increase of thiol levels in both cell lines was observed. Following cell exposure to metallic NPs, the expression of the tranferrin receptor/CD71 was decreased in both cells by iron oxide NPs, but only in MDCK cells by titanium dioxide NPs. The tight association, then subsequent release of NPs by MDCK and LLC-PK kidney epithelial cells, showed that following exposure to the NPs, only MDCK cells could release iron oxide NPs, whereas both cells released titanium dioxide NPs. No transfer of any solid-core NPs across the cell layers was observed.