[Evaluating the effectiveness of child lead poisoning prevention programs]. / Evaluation des résultats d'actions de prévention du saturnisme infantile.

PROBLEM: A multi annual screening and prevention program against lead poisoning was implemented in a suburb of the Paris area. We attempted to assess the effectiveness of this program based on data available from children screening and follow-up. METHODS: Indicators of effectiveness included the evolution of blood lead levels at screening and the frequency of secondary increases in blood lead levels. Buildings inclusion dates were used to control for the increasing selection of less exposed children. RESULTS: A total of 3,660 children were screened between 1992 and 2000. We observed a regular decrease in blood lead levels at screening, in the highest blood lead levels obtained for each child and in the proportion of children whose blood lead levels increased after screening: the proportion of children with initial blood lead levels >=15 micro g/dl fell from 17.4% in the 1992-1996 period to 4.1% in the 1997-2000 period. A multivariate analysis taking into account the first year that children were screened in a given building showed that less exposed children were included over time, but found also an additional independent decrease in blood lead levels that can be related to the effectiveness of prevention efforts. A "building by building" analysis of 30 buildings where more than 20 children were located over the whole study period confirmed that the incidence of lead poisoning decreased within most of these buildings. CONCLUSIONS: Taking into account buildings'inclusion dates makes it possible to distinguish program effectiveness from the consequences of including less exposed children The effectiveness of preventive actions is associated with several interacting factors, including the participation of families and the active involvement of local technical staff and policy makers. The finding that the decrease in blood lead levels leveled off after 1997 calls for further actions.

Unusual potency of BN 80915, a novel fluorinated E-ring modified camptothecin, toward human colon carcinoma cells.

BN 80915 is the lead compound from a novel class of E-ring modified camptothecin analogues, the homocamptothecins, which show potent antitumor activities in animal models. Here, we report that BN 80915 induces up to 2-fold more cleavable complexes between plasmid DNA and purified human topoisomerase I than SN-38 and camptothecin. BN 80915 also induces DNA-topoisomerase I complexes in living HT-29 colon carcinoma cells, as shown by the in vivo link assay. BN 80915 is an extremely potent inducer of DNA-protein complexes in these cells starting at a concentration of 5 nM in the media. BN 80915 is clearly more potent than SN-38, because at least 20 times more SN-38 is needed to induce comparable levels of cleavable complexes. Kinetic experiments show that BN 80915 induces cleavable complexes within minutes that remain stable for at least 6 h in the presence of drug. Whereas the majority of the complexes are reversed within 15 min after drug removal, a substantial fraction (30%) persists for at least 4 h, in contrast with SN-38-treated cells, where all complexes have disappeared by this time. BN 80915 shows strong antiproliferative effects toward HT-29 cells with an IC50 of 0.3 nM compared with 20 nM for SN-38 and 40 nM for topotecan. BN 80915 is also potent against other colon carcinoma cells as well as toward cells growing in three dimensions as multicellular spheroids. HL-60 cells expressing functional P-glycoprotein or multidrug resistance protein show no cross-resistance toward BN 80915. Taken together, our results show that BN 80915 is unusually potent toward human colon carcinoma cells because of the formation of high levels of stable, covalent DNA-topoisomerase complexes.

The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison.

BN 80915, a lead compound of the homocamptothecin (hCPT) family, has entered clinical trials. BN 80915 is a difluoro-hCPT where the six-membered alpha-hydroxylactone ring of camptothecin (CPT) is replaced by a seven-membered beta-hydroxylactone ring. Preclinical data reported here show that in spite of the modification to the crucial E-ring of CPTs, BN 80915 retains topoisomerase I poisoning activity as shown in living HT29 cells as well as in cell-free assays, where BN 80915 always performs better than SN-38 or TPT. In antiproliferative assays BN 80915 is also very potent as evidenced by IC50s values consistently lower than those of SN38 in sensitive cell lines as well as in their related multidrug-resistant lines overexpressing P-glycoprotein or multidrug resistance-associated protein. Furthermore, in human plasma, in contrast to CPT analogs, the hydrolysis of BN 80915 is slow, leading to improved plasma stability, and irreversible, thus avoiding toxicity related to the accumulation of active principle during excretion in the urinary tract. These findings may account for the good in vivo efficacy observed in PC3 xenograft experiments where BN 80915 administered orally at very low doses doubled the tumor growth delay in comparison to CPT-11 administered i.p. Altogether, these results strongly support further development of BN 80915.

Homocamptothecin, an E-ring-modified camptothecin, exerts more potent antiproliferative activity than other topoisomerase I inhibitors in human colon cancers obtained from surgery and maintained in vitro under histotypical culture conditions.

Topoisomerase I (Topo I) is overexpressed in cancer colon tissues compared with normal colon tissues. Several anti-Topo I inhibitors are already successfully used in the clinic. We illustrate here the antiproliferative activity of a new class of Topo I inhibitors, i.e., E-ring-modified camptothecins with enhanced lactone stability (L. Lesueur-Ginot et al., Cancer Res., 59: 2939-2943, 1999). Forty-three human colon cancers were obtained from surgical resection and maintained under organotypical culture conditions for 48 h. Cell proliferation was assessed in these ex vivo tumor tissue cultures by tritiated thymidine autoradiography. As a validation of the methodology, we first analyzed in our model the antiproliferative activity of two clinically active topoisomerase II (Topo II) inhibitors, Adriamycin and etoposide, which are not active for colon cancers; and three Topo I inhibitors, camptothecin (CPT) and two clinically active compounds (especially for colon cancers), i.e., topotecan and the active metabolite of irinothecan, SN-38. We then compared the antiproliferative activity of CPT, topotecan, and SN-38 against those of two investigational E-ring-modified camptothecins, i.e., BN80245 and BN80915. Three concentrations (1, 10, and 100 nM) were studied for each compound. The results indicate that the three Topo I inhibitors used as references, i.e., CPT, irinothecan, and SN-38, were much more active than the two Topo II inhibitors, i.e., Adriamycin and etoposide, with SN-38 being the most efficient. The two investigational compounds BN80245 and BN80915 exerted higher antiproliferative activity than the three anti-Topo I reference compounds, with the highest activity observed for BN80915.

BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II.

BN 80927, a novel homocamptothecin derivative, inhibits both topoisomerase I and topoisomerase II mediated DNA relaxation and shows pronounced cytotoxicity against HT29, SKOV-3, DU145 and MCF7 human tumor cell lines.

Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties.

Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered beta-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of the naturally occurring six-membered alpha-hydroxylactone of CPT. This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma. Biological testing against CPT revealed that, instead of being detrimental, the modified lactone of hCPT has a positive impact on topoisomerase I (Topo I) poisoning properties. In vitro tests showed hCPT to fully conserve the ability to stabilize Topo I-DNA cleavage complexes and to stimulate a higher level of DNA cleavage than CPT. A similar trend toward improvement was also observed in antiproliferative assays with human tumor cell lines (including cells overexpressing P-glycoprotein). In two distinct in vivo models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT was found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast equilibrium of CPT, may account for its good in vivo activity. Overall, these results provide evidence that a highly reactive lactone is not a requisite for the Topo I-mediated antitumor activity of CPT analogues, and that hCPT is an interesting pharmacological tool with improved solution behavior as well as a promising new template for the preparation of more efficacious Topo I poisons.

Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues.

Homocamptothecin (hCPT), a camptothecin (CPT) analogue with a seven membered beta-hydroxylactone which combines enhanced plasma stability and potent topoisomerase I (Topo I)-mediated activity, is an attractive template for the elaboration of new anticancer agents. Like CPT, hCPT carries an asymmetric tertiary alcohol and displays stereoselective inhibition of Topo I. The preparation and biological screening of racemic hCPT analogues are described. The 10 hCPTs tested were better Topo I inhibitors than CPT. Fluorinated hCPTs 23c, d,f,g were found to have potent cytotoxic activity on A427 and PC-3 tumor cell lines. Their cytotoxicity remained high on the K562adr and MCF7mdr cell lines, which overexpress a functionally active P-glycoprotein. Fluorinated hCPTs were more efficacious in vivo than CPT on HT-29 xenografts. In this model, a tumor growth delay of 25 days was reached with hCPT 23g at a daily dose of 0.32 mg/kg, compared to 4 days with CPT at 0.625 mg/kg. Thus difluorinated hCPT 23g warrants further investigation as a novel Topo I inhibitor with high cytotoxicity toward tumor cells and promising in vivo efficacy.

[Health and violence as perceived by young people, a study of the Parisian region]. / Santé et violences perçues par les jeunes, une étude en région parisienne.

We know better the violences made by the youngs than those they suffer from. The purpose of this study is to assess, as for a city surrounding Paris, the prevalence of the violences they felt and its relation with the psychic uneasiness. Some 344 youngs (from 15 to 25 years old) selected in the city, have filled in an autoquestionnaire. It has shown that 61.6% of them have already suffered from violences, among them 44.5% from adults and what is more from institutional adults. 13.7% of the selected youngs were victims of regular violences in school sphere and 12.8% in urban environment. The expression of a psychic uneasiness is linked to the previous violences they have felt. The feeling of call for help by a psychologist or a psychiatrist is in relation with the past psychic discomfort and not with the past suffered violences.

[Cellular senescence and survival of T lymphocytes]. / Sénescence cellulaire et survie des lymphocytes T.

In order to study cellular senescence in T lymphocytes and its link with aging, we have undertaken long-term cultures from adult individuals (aged from 20 to 40) and centenarians. The proliferative advantage of CD4+ over CD8+ T cells is reversed after the second stimulation. Periodically stimulated cultures remained exponentially growing during nearly 200 days, whereas 2 of them that were continued for 300 days stopped proliferating. However, once this phase of senescence is reached, the cells do not die out. Six other cultures remained viable for 34 months without proliferation but with conservation of the cell number. Three of these cultures have clonal karyotypic abnormalities: trisomy 2 and telomeric fusions.

[Screening for lead poisoning in children by measuring lead levels in housing: a study of the Paris region]. / Dépistage du saturnisme infantile à partir de la recherche de plomb dans l'habitat: une étude en région parisienne.

Screening programs for lead poisoning in France rely usually on the preliminary identification of risk factors among children seen in Maternal and Child Health (MCH) clinics. To assess the potential relevance of screening strategies based on the quantification of exposure to lead in housing, we estimated first the prevalence of exposure to lead in a representative sample of older buildings, then the prevalence of lead poisoning among children living in those buildings where high levels of lead had been found. Exposure to lead was measured in dust and paint samples collected in hallways and other collective areas of the buildings. Venous blood samples were collected from the children aged 10 months to 6 years residing in buildings where lead exceeded 1.5 g/kg in paint samples or 1000 micrograms/m2 in dust samples. Paint and dust samples were collected in 137 buildings: 74% presented high dust and/or paint lead contents. Blood samples were collected from 145 out of a total of 189 children residing in these buildings: blood lead levels (PbB) were higher than or equal to 10 micrograms/dl for 65% of these children; 29% were higher than or equal to 15 micrograms/dl, 16% higher than or equal to 20 micrograms/dl. Out of 42 children with PbB > or = 15 micrograms/dl, 21 had not been previously identified through the screening program conducted in local MCH clinics. Clinic-based and environment-based screening appeared to be complementary. It seems thus justified to develop screening strategies based on the assessment of exposure to lead in the environment.

Genetic associations with human longevity at the APOE and ACE loci.

In an effort to dissect the genetic components of longevity, we have undertaken case-control studies of populations of centenarians (n = 338) and adults aged 20-70 years at several polymorphic candidate gene loci. Here we report results on two genes, chosen for their impact on cardiovascular risk, encoding apolipoprotein E (ApoE), angiotensin-converting enzyme (ACE). We find that the epsilon 4 allele of APOE, which promotes premature atherosclerosis, is significantly less frequent in centenarians than in controls (p < 0.001), while the frequency of the epsilon 2 allele, associated previously with type III and IV hyperlipidemia, is significantly increased (p < 0.01). A variant of ACE which predisposes to coronary heart disease is surprisingly more frequent in centenarians, with a significant increase of the homozygous genotype (p < 0.01). These associations provide examples of genetic influences on differential survival and may point to pleiotropic age-dependent effects on longevity.

Nosocomial outbreaks due to amikacin-resistant tobramycin-sensitive Acinetobacter species: correlation with amikacin usage.

Fifty-seven patients in the Val-de-Grâce hospital were infected or colonized with amikacin-resistant, tobramycin-sensitive Acinetobacter spp. between January 1985 and December 1987. This resistance phenotype was attributed to the recently described 3'-O-aminoglycoside phosphotransferase (APH(3')-VI), on the basis of substrate profile and DNA-DNA hybridization, and was mainly encountered in various biotypes of A. baumannii isolated from patients. It was also encountered in saprophytic A. johnsonii isolates from the hands of 11 healthy workers among the medical staff, which provided evidence for the dissemination of an epidemic gene among different biotypes and species of Acinetobacter. A retrospective epidemiological survey showed a significant correlation between amikacin consumption and case incidence in the wards where cross-infection had occurred.

[Previous sports history and risk of ischemic heart disease in a male professional group. The Paris Prospective Study I]. / Antécédents sportifs et risque de cardiopathies ischémiques dans un groupe professionnel masculin. L'Etude Prospective Parisienne I.

The association between individual history of sports activity and cardio-ischemic risk is studied in the population of the Paris Prospective Study I; 6,941 male subjects of the same professional group, aged 42 to 53 years, free of ischemic heart disease and nondiabetic were examined and questioned about their sports history. After a 6.5 year mean follow-up, 234 cases of ischemic heart disease were observed. The subjects practising sports (n = 918), have lower levels of blood pressure, cigarette consumption and corpulence than the other subjects and their relative risk of ischemic heart disease is equal to 0.67 (95% confidence interval: (0.43; 1.04). The ex-sportsmen (n = 4,469) have an ischemic heart disease incidence identical to that of subjects who never practised sports (n = 1,554) and differ only from the later in a slightly higher cigarette consumption. 3,472 subjects were re-examined 4 years after their entrance in the study; the 229 subjects who, during that period, stopped their sports activity have a systolic blood pressure level and tobacco consumption significantly higher at the end of the period but also at the initial exam, than those who continued (n = 337). These results suggest that, in this population, the subjects who keep up with some sports activity after 40 years of age, may have a reduced risk of ischemic heart disease, but they constitute a selected group for some risk factors. They illustrate the difficulty of interpreting observation results concerning the role of sports activity in the prevention of ischemic heart disease.

Induction of hemoglobin synthesis in human leukemic K 562 cells by adriamycin.

The antitumor compound adriamycin was found to induce differentiation-associated properties in human erythroleukemia K 562 cells. Studies on the relationship between drug concentration and the appearance of hemoglobin demonstrated that the more the rate of cell division was reduced during the 4 days of exposure, the higher was the accumulation of hemoglobin per cell. Considering the variation in the intracellular protein content during the response, it appears that adriamycin (40 nM) stimulated the synthesis of both hemoglobin and non-hemoglobin proteins while hemin, a well-known erythroid inducer, specifically increased hemoglobin synthesis. In addition, the lack of cell growth was associated with a recruitment of benzidine-positive cells. In contrast to hemin, adriamycin did not modify the electrophoretic pattern found in untreated cells.