Sex differences in urinary levels of several biological indicators of exposure: a simulation study using a compartmental based toxicokinetic model

Toxicokinetic modeling is a useful tool to describe or predict the behavior of a chemical agent in the human or animal organism. A general model based on four compartments was developed in a previous study in order to quantify the effect of human variability on a wide range of biological exposure indicators. The aim of this study was to adapt this existing general toxicokinetic model to three organic solvents, which were methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1,-trichloroethane, and to take into account sex differences. We assessed in a previous human volunteer study the impact of sex on different biomarkers of exposure corresponding to the three organic solvents mentioned above. Results from that study suggested that not only physiological differences between men and women but also differences due to sex hormones levels could influence the toxicokinetics of the solvents. In fact the use of hormonal contraceptive had an effect on the urinary levels of several biomarkers, suggesting that exogenous sex hormones could influence CYP2E1 enzyme activity. These experimental data were used to calibrate the toxicokinetic models developed in this study. Our results showed that it was possible to use an existing general toxicokinetic model for other compounds. In fact, most of the simulation results showed good agreement with the experimental data obtained for the studied solvents, with a percentage of model predictions that lies within the 95% confidence interval varying from 44.4 to 90%. Results pointed out that for same exposure conditions, men and women can show important differences in urinary levels of biological indicators of exposure. Moreover, when running the models by simulating industrial working conditions, these differences could even be more pronounced. In conclusion, a general and simple toxicokinetic model, adapted for three well known organic solvents, allowed us to show that metabolic parameters can have an important impact on the urinary levels of the corresponding biomarkers. These observations give evidence of an interindividual variablity, an aspect that should have its place in the approaches for setting limits of occupational exposure.

Therapeutic nanoparticles in clinics and under clinical evaluation.

This article reviews nanoparticulate-chemotherapeutic systems that have been developed for human therapy, considering the components of the nanoparticles, the therapeutic agents associated with the nanoparticles and the clinical indications these therapeutic nanoparticles have been developed for. In this evaluation we have put into perspective the types of nanomaterials and their therapeutic indications. We have reviewed the nanoparticulate-chemotherapeutic systems that have been published, approved and marketed and that are currently in clinical use. We have also analyzed the nanoparticulate-chemotherapeutic systems that are in clinical trials and under preclinical development.

Solvent vapours in incubators: a source of exposure among neonates?

Hygiene practices in neonatal units require the use of disinfecting solutions containing ethanol or isopropanol. Newly disinfected hands or soaked swabs introduced inside the incubators may emit vapours leading to alcohol exposures to the neonates. Alcohol emissions from hands and other occasional sources (e.g. soaked disinfecting swabs) lead to measurable levels of vapours inside incubators. Average isopropanol and ethanol concentrations ranging from 33.1 to 171.4 mg/m(3) (13.8 to 71.4 ppm) and from 23.5 to more than 146 mg/m3 (9.8 to > 6 ppm) respectively were measured inside occupied incubators (n = 11, measurement time about 230 min) in a neonatal unit of the Centre Hospitalier Universitaire Vaudois in Lausanne during regular activity. Exposure concentrations in a wide range of possible situations were then investigated by modeling using the one-box dispersion model. Theoretical modeling suggested typical isopropanol peaks and average concentrations ranging between 10(2) and 10(3) mg/m(3) (4.10(1) to 4.10(2)ppm), and 10(1) to 10(2) mg/m(3) (4 to 4.10(1) ppm), respectively. Based on our results we suggest several preventive measures to reduce the neonates' exposures to solvent vapours.

EGASP: the human ENCODE Genome Annotation Assessment Project

Background: Non-long terminal repeat (non-LTR) retrotransposons have contributed to shaping the structure and function of genomes. In silico and experimental approaches have been used to identify the non-LTR elements of the urochordate Ciona intestinalis. Knowledge of the types and abundance of non-LTR elements in urochordates is a key step in understanding their contribution to the structure and function of vertebrate genomes. Results: Consensus elements phylogenetically related to the I, LINE1, LINE2, LOA and R2 elements of the 14 eukaryotic non-LTR clades are described from C. intestinalis. The ascidian elements showed conservation of both the reverse transcriptase coding sequence and the overall structural organization seen in each clade. The apurinic/apyrimidinic endonuclease and nucleic-acid-binding domains encoded upstream of the reverse transcriptase, and the RNase H and the restriction enzyme-like endonuclease motifs encoded downstream of the reverse transcriptase were identified in the corresponding Ciona families. Conclusions: The genome of C. intestinalis harbors representatives of at least five clades of non-LTR retrotransposons. The copy number per haploid genome of each element is low, less than 100, far below the values reported for vertebrate counterparts but within the range for protostomes. Genomic and sequence analysis shows that the ascidian non-LTR elements are unmethylated and flanked by genomic segments with a gene density lower than average for the genome. The analysis provides valuable data for understanding the evolution of early chordate genomes and enlarges the view on the distribution of the non-LTR retrotransposons in eukaryotes.

Sceaux détachés (originaux en cire), cachets, armoiries, jetons et médailles, dessinés ou gravés. XI 356 numéros (ex-libris armoriés, sceaux dessinés ou gravés, cachets, armoiries, dessins de jetons et médailles, etc.).

Contient : N° 53 Sceau de Catherine d'Alençon, duchesse de Bavière (1416) ; Nos 56 et 57 Sceaux de Jean, duc de Calabre et de Lorraine (31 octobre 1465) et de son fils aîné ; N° 58 Sceau de Marguerite, reine d'Angleterre (1470) ; N° 59 Sceau de Bernardin Bochetel, évêque de Rennes (1564) ; N° 61 « S. Petri, Dei gratia archiepiscopi Tholosani » [Pierre V de Lion ?] ; Nos 62 et 64 Sceau de Robert d'Alençon, comte du Perche (1370 et 1375) ; Nos 72 et 81 Médailles du roi René (dessins) ; N° 73 Sceau de Jeanne, reine de Jérusalem, Sicile et Aragon (1498), avec contre-sceau ; N° 74 Sceau et contre-sceau de Louis de France, duc d'Anjou et roi de Sicile ; N° 75 Sceau d'Isabelle, comtesse du Maine et de Guise (1462), avec contresceau ; N° 76 Sceau et contre-sceau de René d'Anjou, roi de Sicile et de Jérusalem ; N° 77 « [S. Nicolai] ducis Calabrie, Lotharingie, A[ndegavie]..., » avec contre-sceau ; N° 78 Sceau de Pierre, comte d'Alençon, seigneur de Fougères, vicomte de Beaumont (1378), avec contre-sceau ; Nos 79 et 82 Sceau et contre-sceau de Louis II, roi de Jérusalem et de Sicile et comte d'Anjou (1407 et 1408) ; Nos 80 et 88 Sceau et contre-sceau de Robert, comte d'Artois ; N° 84 « S. novum Ludovici, regis Fran. filii, ducis Andegavensis et comitis Cenomannensis, » avec contre-sceau (1374) ; N° 85 Sceau et contre-sceau de Catherine, fille aînée du duc d'Alençon, « comtesse de Montfort, dame de Sonois » ; N° 86 Sceau et contre-sceau de Charles, comte du Maine (1451) ; N° 87 « Scel René d'Anjou, chlr., baron et s. de Mézières et de Thury, » avec contre-sceau ; N° 89 Sceau de Yolande reine de Jérusalem et de Sicile (1428) ; N° 94 Sceau d'Henri de Carinthie, évêque de Troyes ; cf. vol. 3101, n° 8 ; N° 101 Sceau de Charles, comte d'Alençon (1361) ; N° 112 Sceau d'Antoine de Cravant, abbé de la Trinité de Vendôme ; cf. vol. 3113, n° 7 ; N° 113 « Sigillum Johannis, episcopi Silvanectensis » [Jean Neveu † 1499, ou Jean Calveau † 1522] ; N° 115 Sceau de Jean de Tinteniac du Percher, abbé de Saint-Aubin († 1525) ; N° 120 « Scel Pierre, bastart d'Alençon » (1419) ; N° 128 « Constras. Ludovici, regis condam Francor. filii, ducis Andegavie et comit. Cenamanie. » ; N° 154 Sceau de Mathieu, évêque de Troyes (1169-1180) ; N° 257 Sceau de René, duc d'Alençon (1478)

Sex differences in urinary levels of several biological indicators of exposure: a human volunteer study

The aim of the study was to quantify the variability on biological indicators of exposure between men and women for three well known solvents: methyl ethyl ketone, 1-methoxy-2-propanol and 1,1,1-trichloroethane. Another purpose was to explore the effect of selected CYP2E1 polymorphisms on the toxicokinetic profile. Controlled human exposures were carried out in a 12m(3) exposure chamber for each solvent separately, during 6h and at half of the threshold limit value. The human volunteers groups were composed of ten young men and fifteen young women, including ten women using hormonal contraceptive. An analysis of variance mainly showed an effect on the urinary levels of several biomarkers of exposure among women due to the use of hormonal contraceptive, with an increase of more than 50% in metabolites concentrations and a decrease of up to 50% in unchanged substances concentrations, suggesting an increase in their metabolism rate. The results also showed a difference due to the genotype CYP2E1*6, when exposed to methyl ethyl ketone, with a tendency to increase CYP2E1 activity when volunteers were carriers of the mutant allele. Our study suggests that not only physiological differences between men and women but also differences due to sex hormones levels can have an impact on urinary concentrations of several biomarkers of exposure. The observed variability due to sex among biological exposure indices can lead to misinterpretation of biomonitoring results. This aspect should have its place in the approaches for setting limits of occupational exposure. [Authors]

Age differences in biological monitoring of chemical exposure: a tentative description using a toxicokinetic model

AIM: Specific factors responsible for interindividual variability should be identified and their contribution quantified to improve the usefulness of biological monitoring. Among others, age is an easily identifiable determinant, which could play an important impact on biological variability. MATERIALS AND METHODS: A compartmental toxicokinetic model developed in previous studies for a series of metallic and organic compounds was applied to the description of age differences. Young male physiological and metabolic parameters, based on Reference Man information, were taken from preceding studies and were modified to take into account age based on available information about age differences. RESULTS: Numerical simulation using the kinetic model with the modified parameters indicates in some cases important differences due to age. The expected changes are mostly of the order of 10-20%, but differences up to 50% were observed in some cases. CONCLUSION: These differences appear to depend on the chemical and on the biological entity considered. Further work should be done to improve our estimates of these parameters, by considering for example uncertainty and variability in these parameters. [Authors]

Archives curieuses de l'histoire de France.... 1re série. Tome 4e

Comprend : Lettres du roy et de la reine-mère au parlement de Paris, au sujet du tumulte arrivé à la porte Sainct-Anthoine de cette Ville, et arrests donnez par cette cour par rapport à ce tumulte et à celui arrivé à Sainct-Médard ; Arret du parlement de Paris, portant qu'il sera fait une procession générale pour l'expiation des sacrilèges commis par les Huguenots dans l'église de Sainct-Médard ; Discours faits dans le parlement de Paris par le duc de Guise et le connétable de Montmorency, sur l'enregistrement de la déclaration du 11 d'avril 1562, sur le tumulte de Vassy, et sur ce qui est arrivé depuis ; Lettre de Catherine de Médicis au cardinal de Chastillon ; Lettre du seigneur baron des Adretz à la Roine-Mère, touchant la mort de La Motte-Gondrin ; Discours des premiers troubles advenus à Lyon, avec l'Apologie pour la ville de Lyon, contre le libelle faucement intitulé : "La Juste et saincte défence de la ville de Lyon", par M. Gabriel de Saconay,... ; Discours sur le saccagement des églises catholiques, par les hérétiques anciens et nouveaux calvinistes, en l'an 1562... par F. Claude de Sainctes,... ; Discours des guerres de la comté de Venayscin et de la Provence, ensemble quelques incidentz... / par le seigneur Loys de Perussiis,...

Adherence to oral anticancer treatment: focus on quality of execution during continuous schema of treatment

Background and objective: Oral anti-cancer treatments have expanded rapidly over the last years. While taking oral tablets at home ensures a better quality of life, it also exposes patients to the risk of sub-optimal adherence. The objective of this study is to assess how well ambulatory cancer patients execute their prescribed dosing regimen while they are engaged with continuous anti-cancer treatments. Design: This is an on-going longitudinal study. Consecutive patients starting an oral treatment are proposed to enter the study by the oncologist. Then they are referred to the pharmacy, where their oral anticancer treatment is dispensed in a Medication Event Monitoring System (MEMSTM), which records date and time of each opening of the drug container. Electronically compiled dosing history data from the MEMS are summarized and used as feedback during semistructured interviews with the pharmacist, which are dedicated to prevention and management of side effects. Interviews are scheduled before each medical visit. Report of the interview is available to the oncologist via an on-line secured portal. Setting: Seamless care approach between a Multidisciplinary Oncology Center and the Pharmacy of an Ambulatory Care and Community Medicine Department. Main outcome measures: For each patient, the comparison between the electronically compiled dosing history and the prescribed regimen was summarized using a daily binary indicator indicating whether yes or no the patient has taken the medication as prescribed. Results: Study started in March 2008. Among 22 eligible patients, 19 were included (11 men, median age 63 years old) and 3 (14%) refused to participate. 15 patients were prescribed a QD regimen, 3 patients a BID and 1 patient switched from QD to BID during follow-up. Median follow up was 182 days (IQR 72-252). Early discontinuation happened in four patients: side effects (n = 1), psychiatric reasons (n = 1), cancer progression (n = 1) and death (n = 1). On average, the daily number of medications was taken as prescribed in 99% of the follow-up days. Conclusions: Execution of the prescribed dosing regimens was almost perfect during the first 6 months. Maintaining this high degree of regimen execution and persistence over time might however be challenging in this population and need therefore to be confirmed in larger and longer follow-up cohort studies.

Acute life-threatening extrinsic allergic alveolitis in a paint controller.

BACKGROUND: Occupational diisocyanate-induced extrinsic allergic alveolitis (EAA) is a rare and probably underestimated diagnosis. Two acute occupational EAA cases have been described in this context, but neither of them concerned hexamethylene diisocyanate (HDI) exposure. AIMS: To investigate the cause of a life-threatening EAA arising at work in a healthy 30-year-old female paint quality controller. METHODS: Occupational medical assessment, workplace evaluation, airborne and biological monitoring and immunodermatological tests. RESULTS: Diagnosis of EAA relied on congruent clinical and radiological information, confirmed occupational HDI exposure and positive IgG antibodies and patch tests. The patient worked in a small laboratory for 7 years, only occasionally using HDI-containing hardeners. While working with HDI for 6 h, she developed breathlessness, rapidly progressing to severe respiratory failure. Workplace HDI airborne exposure values ranged from undetectable levels to 4.25 p.p.b. Biological monitoring of urinary hexamethylene diamine in co-workers ranged from <1.0 to 15.4 μg/g creatinine. Patch tests 8 months later showed delayed skin reaction to HDI at 48 h. Subsequent skin biopsy showed spongiotic dermatitis with infiltration of CD4(+) and CD8(+) T cells. CONCLUSIONS: We believe this is the first reported case of acute life-threatening EAA following exposure to HDI. Low concentrations of airborne HDI and relatively high urinary hexamethylene diamine suggest significant skin absorption of HDI could have significantly contributed to the development of this acute occupational EAA.