The causes of cancer in France.

BACKGROUND: While external factors are responsible for many human cancers, precise estimates of the contribution of known carcinogens to the cancer burden in a given population have been scarce. METHODS: We estimated the proportion of cancer deaths which occurred in France in 2000 attributable to known risk factors, based on data on frequency of exposure around 1985. RESULTS: In 2000, tobacco smoking was responsible for 23.9% of cancer deaths (33.4% in men and 9.6% in women), alcohol drinking for 6.9% (9.4% in men and 3.0% in women) and chronic infections for 3.7%. Occupation is responsible for 3.7% of cancer deaths in men; lack of physical activity, overweight/obesity and use of exogenous hormones are responsible for 2%-3% of cancer deaths in women. Other risk factors, including pollutants, are responsible for <1% of cancer deaths. Thus, known risk factors explain 35.0% of cancer deaths, and 15.0% among never smokers. CONCLUSIONS: While cancer mortality is decreasing in France, known risk factors of cancer explain only a minority of cancers, with a predominant role of tobacco smoking.

The debate on the use of linear no threshold for assessing the effects of low doses.

From December 2004 to July 2005, three reports on the effects of low doses of ionising radiation were released: ICRP (2004), the joint report of the French Academies of Science and Medicine (Tubiana et al 2005), and a report from the American Academy of Sciences (BEIR VII 2005). These reports quote the same recent articles on the biological effects of low doses, yet their conclusions diverge. The French report concludes that recent biological data show that the efficacy of defense mechanisms is modulated by dose and dose rate and that linear no threshold (LNT) is no longer plausible. The ICRP and the BEIR VII reports recognise that there are biologic arguments against LNT but feel that there are not sufficient biological proofs against it to change risk assessment methodology and subsequent regulatory policy based on LNT. They point out the remaining uncertainties and the lack of mechanistic explanations of phenomena such as low dose hyperlethality or the adaptive response. In this context, a critical analysis of the available data is necessary. The epidemiological data and the experimental data challenge the validity of the LNT hypothesis for assessing the carcinogenic effect of low doses, but do not allow its exclusion. Therefore, the main criteria for selecting the most reliable dose-effect relationship from a scientific point of view should be based on biological data. Their analysis should help one to understand the current controversy.

Recent reports on the effect of low doses of ionizing radiation and its dose-effect relationship.

Recently, the risk associated with low doses of ionizing radiation has gained new interest. Here, we analyze and discuss the major differences between two reports recently published on this issue; the report of the French Academy of Sciences and of the French Academy of Medicine published in March 2005, and the BEIR VII-Phase 2 Report of the American National Academy of Sciences published as a preliminary version in July 2005. The conclusion of the French Report is that the linear no-threshold relationship (LNT) may greatly overestimate the carcinogenic effect of low doses (<100 mSv) and even more that of very low doses (<10 mSv), such as those delivered during X-ray examinations. Conversely, the conclusion of the BEIR VII report is that LNT should be used for assessing the detrimental effects of these low and very low doses. The causes of these diverging conclusions should be carefully examined. They seem to be mostly associated with the interpretation of recent biological data. The point of view of the French Report is that these recent data are incompatible with the postulate on which LNT is implicitly based, namely the constancy of the carcinogenic effect per unit dose, irrespective of dose and dose rate.

[Breast cancer: dangers of alleged certainties]. / Cancer du sein: danger des certitudes prétendues.

The artificial increase of breast cancer incidence is estimated as amounting to 30,000 new cases in the year 2000 in France. This increase would be attributable to a 1.2% lack of specificity for the whole range of diagnostic procedures. Sociologically, it appears that the Hippocratic devise "primum nil nocere" ("first don't harm") has been replaced today by "primum agere" ("act first"). Professionals should give information about both limitations and risks of screening. From an ethical point of view, screening programs justify themselves arguing that "there can't be harm in doing good". Absence of alternative strategies is not a sufficient argument for justifying screening with its uncertain consequences.

Identification of the cytochrome P450 enzymes involved in the metabolism of domperidone.

The objective was to identify the major cytochrome P450 enzyme(s) involved in the metabolism of domperidone. Experiments were performed using human liver microsomes (HLMs), recombinant human cytochrome P450 enzymes, cytochrome P450 chemical inhibitors and monoclonal antibodies directed against cytochrome P450 enzymes. Four metabolites were identified from incubations performed with HLMs and excellent correlations were observed between the formation of domperidone hydroxylated metabolites (M1, M3 and M4), N-desalkylated domperidone metabolite (M2) and enzymatic markers of CYP3A4/5 (r2 = 0.9427, 0.951, 0.9497 and 0.8304, respectively). Ketoconazole (1 microM) decreased the formation rate of M1, M2, M3 and M4 by 83, 78, 75 and 88%, respectively, whereas the effect of other inhibitors (quinidine, furafylline and sulfaphenazole) was minimal. Important decreases in the formation rate of M1 (68%), M2 (64%) and M3 (54%) were observed with anti-CYP3A4 antibodies. Formation of M1, M2 and M3 in HLMs exhibited Michaelis-Menten kinetics (Km: 166, 248 and 36 microM, respectively). Similar Km values were observed for M1, M2 and M3 when incubations were performed with recombinant human CYP3A4 (Km: 107, 273 and 34 microM, respectively). The data suggest that CYP3As are the major enzymes involved in the metabolism of domperidone.

[Breast cancer detection and medicalization of public health]. / Dépistage du cancer du sein et médicalisation en santé publique.

The aim of reducing breast cancer mortality announced in the report on health in France published in 1994 strongly implicated the promotion of screening and early surgical treatment. However, this mortality has not evolved significantly in France, although more and more cancers have been found and operated upon. The increased prevalence rates of histological diagnoses of breast cancer obtained from the studies of autopsies published has shown that the screening has discovered non-terminal, benign cancers. It has been estimated that 120 of the surgical operations conducted per day in France in 1999 have been carried out to remove non-terminal, benign cancers. Public health has an ethical responsibility to face in terms of the allocation of resources and must remain vigilant in order to avoid excessive screening and unnecessary interventions.

Most ten-year-old children with negative or unknown histories of chickenpox are immune.

To evaluate the proportion of children to vaccinate against varicella in a catch-up program targeting 9- to 10-year-old children, a study was conducted among children age 10 years to assess the age-specific incidence of varicella and document the immunity against varicella in those with negative or unknown chickenpox history. Of the latter 62% were seropositive for varicella.

Importance of attributable risk in monitoring adverse events after immunization: hepatitis B vaccination in children.

OBJECTIVES: Most vaccine safety data present only the postvaccination incidence of all adverse events rather than an estimate of attributable risk. This study sought to illustrate the difference between the 2 estimates with data from a hepatitis B immunization program. METHODS: The incidence of health problems occurring before and after each dose of hepatitis B vaccine in a cohort of 1130 children were compared. RESULTS: Although 47.5% of all children reported an adverse event during the 4 weeks following each of the 3 doses, adverse events attributable to immunization occurred in only 10.6% of children. CONCLUSIONS: Postimmunization incidence systematically overestimates the risk of adverse events. Estimating actual attributable risk is necessary to avoid false beliefs regarding immunization.

Opinions of Quebec parents and vaccinators on the usefulness of chickenpox vaccine.

BACKGROUND: A chickenpox vaccine was recently licensed in Canada. Because this vaccine has caused some controversy within the health care profession, studies among Quebec parents and vaccine providers were carried out, surveying their opinions concerning chickenpox vaccination. METHODS: Three studies among parents of preadolescents, parents of two-year-old children completely or incompletely vaccinated and vaccinators were completed. The studies asked for opinions concerning the usefulness of vaccinating children against chickenpox. RESULTS: The majority of parents of preadolescents (56%), and parents of two-year-old children completely (64%) and incompletely vaccinated (60%) favoured chickenpox vaccination. Among vaccinators, 53% of paediatricians, 37% of general practitioners and 33% of nurses considered universal vaccination of young children to be useful. A greater proportion of health care professionals were in favour of a policy of vaccinating groups at risk, such as susceptible adolescents (86%, 75% and 58%, respectively). There was a positive association between the perceived severity of chickenpox and the potential usefulness of the vaccine. CONCLUSION: Quebec parents are more favourably disposed to chickenpox vaccine than vaccine providers. In contrast, strategies targeting susceptible groups would be generally well received by health care professionals. A considerable amount of work will be needed to convince vaccinators of the benefits of a universal childhood vaccination against chickenpox.

A pharmacokinetic study of amoxycillin in febrile beagle dogs following repeated administrations of endotoxin.

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 microg/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one-compartment model with lag-time for absorption using an iterative two-stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 microg/kg endotoxin (0.209 vs. 0.140 L/h kg, P < 0.05) and 20 microg/kg endotoxin (0.214 vs. 0.075 L/h kg, P < 0.05). As a result of this, the area under curve for the 2 and 20 microg/kg endotoxin groups increased significantly 100.4 vs. 149.4 microg h/mL (P < 0.05) and 99.2 vs. 277.7 microg h/mL (P < 0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re-evaluated using a febrile animal model to avoid improper dose administration.

Neutron RBE for induction of tumors with high lethality in Sprague-Dawley rats.

The effectiveness of fission neutrons is compared to that of gamma rays and X rays with regard to the induction of malignancies in male Sprague-Dawley rats. The analysis is based on autopsy results. It is focused on tumors that tend to be present in animals dying early, which is indicative of a high degree of lethality. The relative biological effectiveness (RBE) is deduced from a comparison of the cumulative hazard functions. Different nonparametric models-the constant relative risk model, a time shift model, and an acceleration model-are employed in the comparison, and the resulting values of RBE are seen to be substantially independent of the choice of model. The results are in good agreement with earlier studies of nonlethal lung tumors in the same series of experiments. At neutron doses of 20 to 60 mGy, the RBE of fission neutrons is about 50.

[Ionizing radiation]. / Rayonnements ionisants.

Everyone is exposed to radiation from natural, man-made and medical sources, and world-wide average annual exposure can be set at about 3.5 mSv. Exposure to natural sources is characterised by very large fluctuations, not excluding a range covering two orders of magnitude. Millions of inhabitants are continuously exposed to external doses as high as 10 mSv per year, delivered at low dose rates, very few workers are exposed above the legal limit of 50 mSv/year, and referring to accidental exposures, only 5% of the 116,000 people evacuated following the Chernobyl disaster encountered doses above 100 mSv. Epidemiological survey of accidentally, occupationally or medically exposed groups have revealed radio-induced cancers, mostly following high dose-rate exposure levels, only above 100 mSv. Risk coefficients were derived from these studies and projected into linear models of risk (linear non-threshold hypothesis: LNT), for the purpose of risk management following exposures at low doses and low dose-rates. The legitimacy of this approach has been questioned, by the Academy of sciences and the Academy of medicine in France, arguing: that LNT was not supported by Hiroshima and Nagasaki studies when neutron dose was revisited; that linear modelling failed to explain why so many site-related cancers were obviously non-linearly related to the dose, and especially when theory predicted they ought to be; that no evidence could be found of radio-induced cancers related to natural exposures or to low exposures at the work place; and that no evidence of genetic disease could be shown from any of the exposed groups. Arguments were provided from cellular and molecular biology helping to solve this issue, all resulting in dismissing the LNT hypothesis. These arguments included: different mechanisms of DNA repair at high and low dose rate; influence of inducible stress responses modifying mutagenesis and lethality; bystander effects allowing it to be considered that individual cellular responses reflected in fact the results of multiple cellular interactions. Following the conclusion of the French Academy of medicine, LNT modelling resulted in public anxiety by changing an hypothetical residual risk at low doses into a real one, calling on regulators, continuously, for a more and more severe control of tiny sources which may result in considerable collective doses when considered as being exposed to billions of people for hundreds of years. Examples were provided that showed that the perception of risk of radioactive sources was not related to the severity of the risk itself but to the importance attributed to the situation by the media. In some instances, such as those resulting from the loss of gammagraphy sources, it resulted in a dangerous underestimate of the necessary remedial actions.

Qualitative and quantitative analyses of psychological distress: methodological complementarity and ontological incommensurability.

Rigorous qualitative and quantitative methodologies have been used for the development of a multidimensional scale dedicated to the measurement of psychological distress. A comparison between the idioms of distress or the cultural forms through which French Quebecois express their distress (qualitative constructs) and the nonorthogonal factors derived from explanatory and higher order factorial analyses (quantitative constructs) illustrates the possibilities of complementarity between qualitative and quantitative approaches. The comparison shows that these two operationalizations of the concept of psychological distress are founded on incommensurable representations of distress. This article concludes that this representational dilemma of distress as a lived language or as an empirical reified entity leads to an ontological and a teleological incommensurability.

Benzyltriphenylphosphonium glutaconaldehyde

The title compound, C(25)H(22)P(+).C(5)H(5)O(2)(-), crystallizes in space group P2(1)/c. The phosphonium cations form zigzag chains with P.P distances of 6.475 (1) and 8.287 (2) A, and are related by inversion centres. Two types of attractive edge-to-face phenyl interactions exist, resulting in a dominant supramolecular motif. The glutaconaldehyde anions occupy the interchain spacing and hold adjacent chains together via multiple C-H.O hydrogen bonds. The bond-length alternation, a parameter which reveals the non-linear optical efficiency at the molecular level, is optimized in the chromophore anion.

Comparative immunogenicity under field conditions of two recombinant hepatitis B vaccines in 8-10-year-old children.

The immunogenicity of two hepatitis B vaccines was compared in 8-10-year-old children immunized in a school program. One year apart, 1129 children received Engerix-B 10 microg vaccine (EB), and 1126 received Recombivax-HB 2.5 microg (RB), following the 0, 1, 6 schedule. Blood samples were collected one month after the third dose. Anti-Hbs were measured by commercial radioimmunoassay. In the EB group, 99.1% of the children seroconverted (>/=2 IU/l) compared to 99.7% in the RHB group (p=0.09). The seroprotection rate (>/=10 IU/l) was similar for both groups: 98.9% in the EB group and 99.2% in the RB group (p=0.66). However, GMCs of anti-HBs were higher in children given EB compared to those given RB (7307 vs. 3800 mIU/ml, p<0.0001). This study showed that both vaccines were highly immunogenic, in the course of a regular field immunization program. However, the difference observed in the antibody levels attained according to the vaccine may play a role in the long-term protection of these children.

Genetic susceptibility to radiations. Which impact on medical practice?

Recent progress especially in the field of gene identification and expression have raised more attention on genetic susceptibility to cancer possibly enhanced by radiation. Radiation therapists are mostly concerned by this question since hypersensitive patients may suffer from adverse effects in normal tissues following a standard radiation therapy and normally sensitive patients could benefit from higher doses of radiation for better treatment of their malignant tumors. Although only a small percentage of individuals are "hypersensitive" to radiation effects, all medical specialists using ionising radiation should be aware of this new progress in medical knowledge. The present paper reviews the main pathologies (diseases, syndromes...) known or strongly suspected to be associated with a hypersensitivity to ionizing radiation. Then the main tests capable of detecting in advance such pathologies are analyzed and compared. Finally guidelines are provided, especially to the radiation therapists to limit the risk of severe complications (or even deaths) for this specific subset of patients suffering from a genetic disorder with a susceptibility to radiations.

[Elaboration and validation of a tool to measure psychological well-being: WBMMS]. / Elaboration et validation d'un outil de mesure du bien-être psychologique: l'EMMBEP.

Psychological well-being scales used in epidemiologic surveys usually show high construct validity. The content validation, however, is less convincing since these scales rest on lists of items that reflect the theoretical model of the authors. In this study we present results of the construct and criterion validation of a new Well-Being Manifestations Measure Scale (WBMMS) founded on an initial list of manifestations derived from an original content validation in a general population. It is concluded that national and public health epidemiologic surveys should include both measures of positive and negative mental health.