Risk assessment of dimethylfumarate residues in dwellings following contamination by treated furniture.

Recently, numerous cases of dermatitis induced by dimethylfumarate (DMFu) have been reported in Europe. DMFu has been used to prevent mold development in various items, although it is not registered as a biocide. In France, from October 2008 to December 2009, more than 100 cases were reported. Despite a ban on articles containing DMFu and the removal of potentially contaminated products, some people were still suffering from dermatitis or other health problems. The French Agency for Food, Environmental and Occupational Health & Safety was mandated to assess whether the existence in the past of DMFu-contaminated items in dwellings could continue to pose a threat to the health of inhabitants. A risk assessment was performed based on the classical risk analysis approach for environmental contaminants. Hazard assessment of DMFu with regard to its sensitizing properties was performed, based on human case reports collected in France between January 2009 and February 2010. For around half of the 132 individual cases reported, the causal link to DMFu was considered at least probable. An Organisation for Economic Co-Operation and Development (OECD) local lymph node assay performed in a study on mice showed strong sensitizing potential for DMFu. Exposure was assessed by measuring DMFu in items sampled in preselected dwellings. These investigations demonstrated that DMFu exposure can persist after removal of the primary contaminated items. We therefore concluded that there was clearly a risk of skin reactions in patients previously sensitized to DMFu. Furthermore, the available data do not support the existence of significant health effects through the respiratory route.

A phase II trial of panobinostat in patients with advanced pretreated soft tissue sarcoma. A study from the French Sarcoma Group.

BACKGROUND: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. METHODS: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. RESULTS: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21-79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10-35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. CONCLUSION: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

[Study of self-reported health of people living near point sources of environmental pollution: a review. First part: health indicators]. / Étude de la santé déclarée par les personnes riveraines de sources locales de pollution environnementale : une revue de la littérature. Première partie : les indicateurs de santé déclarée.

BACKGROUND: Epidemiological studies have investigated the health impacts of local sources of environmental pollution using as an outcome variable self-reported health, reflecting the overall perception interviewed people have of their own health. This work aims at analyzing the advantages and the results of this approach. A first step focused on describing the indicators. METHODS: The literature on indicators of self-reported health was reviewed, leading to a discussion on data collection, selection of health effects, data processing, and construction of indicators. RESULTS: The literature review concerned 51 articles. The use of self-reported health indicators allowed the studies to take into account the health concerns and complaints of populations exposed to environmental pollution. Various indicators of self-reported health were used in the studies. They measured physical, psychological and general dimensions of health. Standardized questionnaires were used less often than ad hoc questionnaires (78% of studies) developed to fit the needs of a given study. Three standardized questionnaires were used more frequently: the MOS Short-Form Health Survey (SF-36) to measure general health perceptions, the General Health Questionnaire (GHQ), and the Symptoms Checklist (SCL-90) to measure psychological distress. CONCLUSION: The choice of self-reported health indicators is a compromise between specificity of the studied health issues within a given environment and standardization of the questionnaires used to measure them. Such standardization is necessary to ensure the validity and the reliability of the information collected across time and situations. The psychometric properties of the measuring questionnaires are rarely estimated or verified when they are used.

[Study of self-reported health of people living near point sources of environmental pollution: a review. Second part: analysis of results and perspectives]. / Étude de la santé déclarée par les personnes riveraines de sources locales de pollution environnementale : une revue de la littérature. Seconde partie : analyse des résultats et perspectives.

BACKGROUND: Epidemiological studies have investigated the health impacts of local sources of environmental pollution using as an outcome variable self-reported health, reflecting the overall perception interviewed people have of their own health. This work aims at analyzing the advantages and the results of this approach. This second part presents the results of the studies. METHODS: Based on a literature review (51 papers), this article presents an analysis of the contribution of self-reported health to epidemiological studies investigating local sources of environmental pollution. It discusses the associations between self-reported health and exposure variables, and other risk factors that can influence health reporting. RESULTS: Studies using self-reported health showed that local sources can be associated with a wide range of health outcomes, including an impact on mental health and well-being. The perception of pollution, especially sensory information such as odors, affects self-reported health. Attitudes referring to beliefs, worries and personal behaviors concerning the source of pollution have a striking influence on reported health. Attitudes can be used to estimate the reporting bias in a biomedical approach, and also constitute the main explanatory factors in biopsychosocial studies taking into account not only the biological, physical, and chemical factors but also the psychological and social factors at stake in a situation of environmental exposure. CONCLUSION: Studying self-reported health enables a multifactorial approach to health in a context of environmental exposure. This approach is most relevant when conducted within a multidisciplinary framework involving human and social sciences to better understand psychosocial factors. The relevance of this type of approach used as an epidemiological surveillance tool to monitor local situations should be assessed with regard to needs for public health management of these situations.

Post natal oestrogen administration stimulates precocious endometrial gland development in the horse.

REASONS FOR PERFORMING STUDY: Fillies completely devoid of endometrial glands (uterine gland knockout; UGKO) would make ideal experimental models in which to study the role of endometrial histotroph in embryogenesis and early fetal development in the mare. HYPOTHESIS: Administration of a synthetic progestagen plus oestrogen to newborn filly foals and, thereafter, at regular intervals to age 6 months, would permanently suppress endometrial gland development. METHODS: Nine half-sister Thoroughbred filly foals were treated, in 3 groups, with: A) the weakly active progestagen, norgestomet, administered from birth to age 6 months, in subcutaneous implant form plus oestradiol valerate and norgestomet i.m. at fortnightly intervals; B) the strongly active oral progestagen, altrenogest, administered daily from birth to age 6 months plus fortnightly injections of oestradiol valerate and norgestomet; C) nothing (untreated controls). Endometrial biopsies were recovered from all fillies at ages 6 months and 2 years to assess the degree of endometrial gland morphogenesis and to determine immunohistochemically the presence or absence of oestrogen and progesterone receptors in the endometrial tissues. RESULTS: Groups B and C showed no endometrial gland development, whereas Group A fillies showed a high degree of endometrial gland development, plus strong staining for both oestrogen and progesterone receptors at age 6 months. All 9 fillies showed full normal endometrial gland morphogenesis, development and function at age 2 years. CONCLUSIONS AND RELEVANCE: While the administration of a strongly active progestagen over-rode the actions of the concomitantly administered oestrogen and suppressed endometrial gland development during the period of administration, treatment with oestradiol valerate together with a weakly active progestagen, stimulated precocious endometrial gland development. Neither steroid was able to create the desired UGKO experimental model and all fillies showed normal endometrial gland development and fertility after puberty. Hence, ovarian oestrogen, not progesterone, appears to be the basic stimulus for endometrial gland morphogenesis in the horse.

Short-term associations between fine and coarse particles and hospital admissions for cardiorespiratory diseases in six French cities.

OBJECTIVES: Little is known about the potential health effects of the coarse fraction of ambient particles. The aim of this study is to estimate the links between fine (PM(2.5)) and coarse particle (PM(2.5-10)) levels and cardiorespiratory hospitalisations in six French cities during 2000-2003. METHODS: Data on the daily numbers of hospitalisations for respiratory, cardiovascular, cardiac and ischaemic heart diseases were collected. Associations between exposure indicators and hospitalisations were estimated in each city using a Poisson regression model, controlling for confounding factors (seasons, days of the week, holidays, influenza epidemics, pollen counts, temperature) and temporal trends. City-specific findings were combined to obtain excess relative risks (ERRs) associated with a 10 mug/m(3) increase in PM(2.5) and PM(2.5-10 )levels. RESULTS: We found positive associations between indicators of particulate pollution and hospitalisations for respiratory infection, with an ERR of 4.4% (95% CI 0.9 to 8.0) for PM(2.5-10 )and 2.5% (95% CI 0.1 to 4.8) for PM(2.5). Concerning respiratory diseases, no association was observed with PM(2.5), whereas positive trends were found with PM(2.5-10), with a significant association for the 0-14-year-old age group (ERR 6.2%, 95% CI 0.4 to 12.3). Concerning cardiovascular diseases, positive associations were observed between PM(2.5) levels and each indicator, although some did not reach significance; trends with PM(2.5-10 )were weaker and non-significant except for ischaemic heart disease in the elderly (ERR 6.4%, 95% CI 1.6 to 11.4). CONCLUSIONS: In accordance with other studies, our results indicate that the coarse fraction may have a stronger effect than the fine fraction on some morbidity endpoints, especially respiratory diseases.

[Measure of premature mortality: comparison of deaths before age 65 and expected years of life lost]. / La mesure de la mortalité prématurée: comparaison des décès avant 65 ans et des années espérées de vie perdues.

BACKGROUND: For many years in France, premature mortality (i.e., deaths before 65 years old) and avoidable deaths have generally been used to monitor health of the population and help to elaborate policies in this area. This paper aims to examine the utility of another indicator of premature mortality, which makes it possible to take into account the impact of deaths, the expected years of life lost (EYLL). METHODS: Mortality data for France in the years 2000 to 2002 were obtained from the Centre for Epidemiology of the Medical Causes of Death. Premature mortality was defined as death before 65 years of age. For the calculation of EYLL, the mortality norm chosen was French-life expectancy for the years 2001 to 2003. In order to study the spatial distribution of the indicators above defined, standardized ratios were calculated for each administrative area, taking France as the reference population. RESULTS: Irrespective of the gender and indicator considered, ranking of the causes emphasized three major groups of pathological conditions, which are strongly distinguished from the others: cardiovascular diseases, malignant neoplasm and injuries. The ranking of causes varied considerably according to the indicator used. The spatial representation of standardized ratios of expected years of life lost and deaths before 65 showed a strong North-South trend. CONCLUSION: The concept of premature mortality is difficult to define and discussions persist on the age limit to use for its quantification. The choice of an indicator strongly depends on the use which one wishes to make. The simple analysis of deaths before 65 years currently used to describe premature mortality in France makes it possible to describe its frequency. The use of a summary measure as EYLL allows to quantify the impact of premature mortality by giving different weights to deaths depending on the age of occurrence. EYLL, thus, seems to be an indicator, which is particularly adapted to decision-making in public health, depending on choices and values one wishes to give preference to.

Influence of breed and oestrous cycle on endometrial gland surface density in the mare.

REASON FOR PERFORMING STUDY: The diffuse noninvasive epitheliochorial equine placenta develops an intimate and complex interdigitation with the maternal endometrium throughout gestation to maximise surface contact and, consequently, optimise nutritional and gaseous maternofetal exchanges. A significant reduction occurs in the surface density of microcotyledons on the placentae of Welsh Pony vs. Thoroughbred mares that may relate to a difference in either the number or density of endometrial glands between these breeds. OBJECTIVES: To examine this hypothesis and to determine the influence of the oestrous cycle upon the development and surface density of endometrial glands. METHODS: Endometrial biopsies were taken under videoendoscopic visual control from the base of a uterine horn from young, fertile, Welsh Pony and Thoroughbred mares at defined stages of the oestrous cycle. Computer-assisted morphometric analysis then permitted the surface density of endometrial glands within the stratum spongiosum to be assessed. CONCLUSIONS: There was a statistically significant reduction in endometrial gland surface density in the Welsh Pony vs. Thoroughbred mares during both oestrus and dioestrus. POTENTIAL RELEVANCE: A substantial upregulation of epidermal growth factor (EGF) mRNA in the epithelial cells lining the apical portions of endometrial glands has been demonstrated in pregnant mares between Days 35 and 40 after ovulation, coincident with the onset of interdigitation between the allantochorion and endometrium to form the microcotyledonary placenta. The increased surface density of endometrial glands noted in the uteri of Thoroughbred mares might account for the greater surface density of placental microcotyledons in this breed.

Endometrial gland surface density and hyperaemia of the endometrium during early pregnancy in the mare.

REASON FOR PERFORMING STUDY: The morphology and surface density of endometrial glands responsible for the nutrition of the placenta requires further study employing computer assisted morphometric analysis. OBJECTIVES: To analyse changes in the morphology and surface density of endometrial glands situated adjacent to, and remote from, the conceptus during the first 30 days of gestation. METHODS: Endometrial biopsies were recovered, under videoendoscopic control, from both nonpregnant and pregnant mares 12 days after ovulation, as well as from pregnant mares on Days 16, 20, 25 and 30 of gestation. One biopsy was taken at the base of the nongravid uterine horn and the other from beneath the conceptus at the base of the gravid horn. The samples were evaluated by computer assisted morphometric analysis to determine the surface area per unit volume (Sv) of endometrial glands in the stratum spongiosum. RESULTS: No differences in morphology or density of the glands were discernable between pregnant and nonpregnant mares on Day 12 day after ovulation. On Day 16, however, the glands beneath the conceptus appeared to be at a significantly lower density than the clearly more tortuous glands at the base of the nongravid horn. Between Days 20 and 30 of gestation the endometrium in direct contact with the conceptus was visibly more reddened and hyperaemic than elsewhere in the uterus. However, the Sv of glands beneath the conceptus had now increased again so they appeared similar to those in the nongravid horn, due mainly to a reduction in the level of stromal oedema in the former. CONCLUSIONS AND POTENTIAL RELEVANCE: The embryo-maternal interactions that are vital during early pregnancy to suppress the cyclical luteolytic cascade and support nidation of the conceptus, were characterised here with local endometrial hyperaemia, histotroph production and a decrease in endometrial gland Sv at the commencement of the stationary phase. Both the components secreted by the endometrial glands and the factors liberated by the conceptus during early pregnancy need further investigation.

[Estimating mortality attribuable to PM10 particles in 9 French cities participating in the European programme Apheis]. / Estimation de la mortalité attribuable aux particules (PM10) dans les 9 villes françaises participant au programme européen Apheis.

The relationship between air pollution and mortality is now admissible with a sufficiently high level of causality proven. This link allows for health impact assessment to be carried out with a significant degree of accuracy, such as the case for the results which are presented here from the nine French cities involved in the Apheis programme. This health impact assessment is based on the methodology developed by the World Health Organization. The number of avoidable deaths is contained between categories ranging from 2.0 to 4.3, 4.0 to 8.9, and from 15.0 to 31.5 per 100,000 inhabitants according to very short term effects, short term effects and long term effects, respectively. There are two scenarios which can be envisioned for the reduction of fine particles levels which are capable of obtaining similar results for both very short term and short term effects. The first involves diminishing the daily concentrations which are above 20 microg/m3 until they reach this value, and the second entails systematically decreasing the daily levels by 5 microg/m3. The first strategy of reducing values to stabilize at 20 microg/m3 has been shown to be the one most favourable and promising for the long term effects. This strategy therefore confirms the reliability and strength of the recommendation formulated at the national level.

[Disability-adjusted life years: an instrument for defining public health priorities?]. / Les "Années de vie ajustées sur l'incapacité": un outil d'aide à la définition des priorités de santé publique?

BACKGROUND: The objective of this paper is the study of a health indicator allowing surveillance and evaluation of the overall health of the Paris population, and providing information to help prioritize possible choices among preventive and curative actions. Moreover, comparison between results obtained for Paris with a global health indicator, "Disability-adjusted life years" (DALYs) and available bibliographical data will enable clarifying some points about summary measures of health. METHODS: The method used is that of the Global Burden of Disease. It allows a ranking of diseases using an indicator called DALYs. This indicator integrates mortality and morbidity components by summing expected years of life lost due to premature mortality and calculated years of healthy life lost. DALYs were calculated using local mortality data and published regional disabilities tables from the World Health Organisation (WHO). RESULTS: There were a total of 242 061 DALYs for Paris for the year 1999. The six leading specific causes are: alcoholic psychosis and dependence (accounting for 6.5% of the total), lung cancers (5.7%), ischaemic hearth disease (4.8%), depression (4.4%), dementias (4.2%), and arthritis (3.9%). Men contributed the majority of DALYs for the first three. For four of the six leading causes, the majority of DALYs came from years lived with disability, rather than mortality. Only for lung cancer and ischaemic hearth disease was the majority of DALYs from years of life lost by mortality. CONCLUSION: The results for Paris are used to illustrate how DALYs can illuminate debates about public health priorities. Such data can inform the population about health condition and provide decision makers with global health indicators. The next step will be to estimate the DALYs from local morbidity data when available, and compare these results to those based on the World Health Organisation tables, which are not sensitive to local results other than those due to mortality. Future steps include further evaluation and development of this method for surveillance, assessment and evaluation of public health actions. However, some of the results obtained with this indicator underline the limits of this kind of analysis.

[The impact of air pollution on health. The "Programme de Surveillance Air et Santé 9 villes" (Air and Health surveillance program in 9 cities)]. / Retentissement de la pollution atmosphérique sur la santé. Le Programme de Surveillance Air et Santé 9 villes.

OBJECTIVES: To quantify the short term effects of air pollution on mortality and hospitalisation for cardiovascular or respiratory disorders in the nine French cities (Bordeaux, Le Havre, Lille, Lyon, Marseille, Paris, Rouen, Strasbourg and Toulouse) of the Surveillance Air et Santé program. METHODS: Data were available on mortality and hospitalisation were available, respectively, from 1990 to 1997 and 1995 to 1999. Exposure data were the concentrations of sulphur dioxide, particles with a diameter of less than or equal to 10 mm, black smoke, nitrogen dioxide, ozone, and carbon monoxide. The analysis assessed the relationships, in each of the cities, between the daily numbers of deaths and hospitalisations and the daily levels of polluting agents, taking into account confounding factors. A combined relative risk was calculated for all the cities. The number of deaths and hospitalisations attributable to air pollution was then estimated for each of the cities, based on the relative risk. RESULTS: Significant relationships were found for mortality, from whatever cause, and for hospitalisations for respiratory disorders in children aged under 15. If the levels of air pollution were reduced to 10 microg/m3 in the nine cities, 2800 premature deaths and 750 hospitalisations for respiratory disorders in children would be avoided, every year. CONCLUSION: Today, it is possible to assess the benefits of reducing air pollution in terms of health in the short term. These analyses would provide a sanitary dimension to the strategies for the reduction of urban pollution on local and European level.

Construction of bicyclo[3.2.1]octanes with four stereogenic centers by organocatalytic domino Michael/Aldol reaction.

An enantio- and diastereoselective organocatalytic domino Michael/Aldol reaction for the direct preparation of synthetically and medicinally relevant bicyclo[3.2.1]octane derivatives with four stereogenic centers, including two quaternary carbons, has been described. The reaction tolerates a large variety of substituents on ß,γ-unsaturated 1,2-ketoesters and cyclic 1,3-ketoesters. It allows for the formation of various bicyclo[3.2.1]octanes in good yields (53-98%), diastereoselectivities (1:1 to 5:1 dr), and enantioselectivities (up to 95:5 ee).

The effects of an advanced uterine environment on embryonic survival in the mare.

REASONS FOR PERFORMING THE STUDY: During embryo transfer (ET) the equine embryo can tolerate a wide degree of negative asynchrony but positive asynchrony of >2 days usually results in embryonic death. There is still confusion over whether this is due to the inability of the embryo to induce luteostasis or to an inappropriate uterine environment. OBJECTIVES: To assess embryo survival and development in an advanced uterine environment. HYPOTHESIS: Embryo-uterine asynchrony, not the embryo's inability to induce luteostasis, is responsible for embryonic death in recipient mares with a >2 days chronologically advanced uterus. METHODS: Experiment 1: Thirteen Day 7 embryos were transferred to the uteri of recipient mares with luteal prolongation, occasioned by manual crushing of their own conceptus, such that donor-recipient asynchrony was between +13 and +49 days. Experiment 2: Day 7 embryos were transferred to recipient mares carrying their own conceptus at Days 18 (n = 2), 15 (n = 2), 14 (n = 4), 12 (n = 4) or 11 (n = 4) of gestation. In addition, Day 8 embryos were transferred to 4 pregnant recipient mares on Day 11 of gestation. RESULTS: No pregnancies resulted following transfer of Day 7 embryos to recipients in prolonged dioestrus with asynchronies between +13 and +49 days. However, the use of early pregnant mares as recipients resulted in 5/20 (25%) twin pregnancies, 4 of which came from the transfer of a Day 8 embryo to a Day 11 recipient. All transferred embryos showed retarded growth, with death occurring in 4/5 (80%). CONCLUSIONS AND POTENTIAL RELEVANCE: The results emphasise the importance of an appropriate uterine environment for embryo growth and the inability of equine embryos to survive transfer to a uterus >2 days advanced even when luteostasis is achieved. It is possible that in normal, non-ET equine pregnancy, embryo-uterine asynchrony may account for some cases of embryonic death.

A randomised phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study).

AIM: To evaluate in a multicentre randomised study the effect on duration of febrile neutropenia (FN), the safety and cost-effectiveness of a single subcutaneous pegfilgrastim injection compared with daily injections of filgrastim after peripheral blood stem cell transplantation in patients receiving high dose chemotherapy for myeloma and lymphoma. METHODS: Patients were randomly assigned to a single dose of pegfilgrastim at day 5 (D5) or daily filgrastim from D5 to the recovery of absolute neutrophil count (ANC) to 0.5 G/L. Duration of FN, of neutrophil and platelet recovery, transfusion and antibiotic requirements were the main end-points of the study. Costs were calculated from D0 until transplant unit discharge. The incremental cost-effectiveness ratio was expressed as the cost per day of FN prevented. Probabilistic sensitivity analysis was performed by non-parametric bootstrap methods. RESULTS: Between October 2008 and September 2009, 10 centres enrolled 151 patients: 80 patients with lymphoma and 71 patients with myeloma. The mean duration of FN was 3.07 days (standard deviation (SD) 1.96) in the pegfilgrastin arm and 3.29 (SD 2.54) in the filgrastim one. Mean total costs were 23,256 and 25,448 euros for pegfilgrastim and filgrastim patients, respectively. There was a 62% probability that pegfilgrastim strictly dominates filgrastim. CONCLUDING STATEMENT: Pegfilgrastim after PBSC transplantation in myeloma and lymphoma is safe, effective when compared with filgrastim and could represent a cost-effective alternative in this setting.

Short-term effects of nitrogen dioxide on mortality: an analysis within the APHEA project.

The short-term effects of nitrogen dioxide (NO(2)) on total, cardiovascular and respiratory mortality in 30 European cities participating in the Air Pollution on Health: a European Approach (APHEA)-2 project were investigated. The association was examined using hierarchical models implemented in two stages. In the first stage, data from each city were analysed separately, whereas in the second stage, the city-specific air pollution estimates were regressed on city-specific covariates to obtain overall estimates and to explore sources of possible heterogeneity. A significant association of NO(2) with total, cardiovascular and respiratory mortality was found, with stronger effects on cause-specific mortality. There was evidence of confounding in respiratory mortality with black smoke and sulphur dioxide. The effect of NO(2) on total and cardiovascular mortality was observed mainly in western and southern European cities, and was larger when smoking prevalence was lower and household gas consumption was higher. The effect of NO(2) on respiratory mortality was higher in cities with a larger proportion of elderly persons in the population and higher levels of particulate matter with a 50% cut-off aerodynamic diameter of 10 mum. The results of this large study are consistent with an independent effect of nitrogen dioxide on mortality, but the role of nitrogen dioxide as a surrogate of other unmeasured pollutants cannot be completely ruled out.