Dramatic Increase in Incidence of Ulcerative Colitis and Crohn's Disease (1988-2011): A Population-Based Study of French Adolescents.

OBJECTIVES: Few data are available to describe the changes in incidence of pediatric-onset inflammatory bowel disease (IBD). The aim of this study was to describe changes in incidence and phenotypic presentation of pediatric-onset IBD in northern France during a 24-year period. METHODS: Pediatric-onset IBD (<17 years) was issued from a population-based IBD study in France between 1988 and 2011. Age groups and digestive location were defined according to the Paris classification. RESULTS: 1,350 incident cases were recorded (8.3% of all IBD) including 990 Crohn's disease (CD), 326 ulcerative colitis (UC) and 34 IBD unclassified (IBDU). Median age at diagnosis was similar in CD (14.4 years (Q1=11.8-Q3=16.0)) and UC (14.0 years (11.0-16.0)) and did not change over time. There were significantly more males with CD (females/males=0.82) than UC (females/males=1.25) (P=0.0042). Median time between onset of symptoms and IBD diagnosis was consistently 3 months (1-6). Mean incidence was 4.4/105 for IBD overall (3.2 for CD, 1.1 for UC and 0.1 for IBDU). From 1988-1990 to 2009-2011, a dramatic increase in incidences of both CD and UC were observed in adolescents (10-16 years): for CD from 4.2 to 9.5/105 (+126%; P<0.001) and for UC, from 1.6 to 4.1/105 (+156%; P<0.001). No modification in age or location at diagnosis was observed in either CD or UC. CONCLUSIONS: In this population-based study, CD and UC incidences increased dramatically in adolescents across a 24-year span, suggesting that one or more strong environmental factors may predispose this population to IBD.

INRS activities on risk assessment of glycol ethers.

The occupational exposure assessment uses data from published sources, from Industry (most often from the producers), and from dedicated occupational exposure data bases, as well as evaluations using the EASE model (Estimation and Assessment of Substance Exposure). Atmospheric concentrations and characteristics of skin contacts are evaluated in different scenarios (such as manufacturing, formulating, main and most polluting uses) and sub-scenarios (e.g. warm water dilution). Air concentrations of EGBE are low during production (most often <0.5 mg/m(3)), incidental excursions being <50 mg/m(3); the "worst-case" mean concentration is proposed as 9 mg/m(3). Skin contact, according to EASE, may be in the range of 0-0.1 mg/cm(2)(day), and should be mitigated by the use of suitable gloves. For formulations of products containing EGBE, air concentrations are evaluated as 10 mg/m(3) and skin contact as 0.19 mg/cm(2)(day). The "reasonable worst case" air concentrations (8-Hr TWA) are assessed at around 11 mg/m(3) (coating industry), from 5 to 20 mg/m(3) in printing activities (depending on the task), and in the 20-70 mg/m(3) range (upper limit 40 mg/m(3) in better controlled situations) for cleaning activities. Skin contact would be around twice the preceding level, i.e., 0.4 mg/cm(2)(day) for coating as well as cleaning activities. EGBE and its major metabolites, 2-butoxyacetaldehyde (2-BAL) and 2-butoxyacetic acid (2-BAA) have been subjected to tests for genetic toxicity tests both in vitro and in vivo. While some positive responses have been obtained, the balance of the evidence indicates that EGBE does not express significant genotoxic activity. There are no epidemiological data investigating a relationship between exposure to EGBE and human cancer. Two carcinogenicity inhalation bioassays have been conducted in rodents, one in rats and one in mice. Significant increases were found in forestomach tumours in female mice and haemangiosarcomas in male mice. No increases in tumour incidences were found in either male or female rats. Mechanistic studies have suggested the crucial involvement in the pathogenesis of haemangiosarcomas of a chain of events consisting of (1) haemolysis due to BAA, followed by (2) hepatic haemosiderin deposition and (3) the subsequent generation of reactive oxygen species within the endothelial cells from which haemangiosarcomas arise. Since human erythrocytes are particularly resistant to the haemolytic effects of BAA, it is extremely unlikely, according to this model, that the haemangiosarcomas observed in male mice will have human significance. Similarly, mechanistic studies on the female mouse forestomach tumours have suggested that these also are not important as an indication of human risk. In vivo, EGBE tested in a continuous breeding study and in repeated dose toxicity tests, did not produced specific effects on reproductive organs or fertility parameters. For developmental toxicity, rats, mice and rabbits were dosed via oral and/or inhalation routes. Foeto- and embryo-toxicity was observed in presence or maternal toxicity (haemolytic anaemia). The data available give plausible support to the hypothesis that this developmental toxicity is a direct consequence of maternal toxicity. There are no epidemiological data investigating a relationship between exposure to EGBE alone and human reproductive effects.

A homogeneous caspase-3 activity assay using HTRF technology.

Caspases are cysteine proteases presenting a conserved active site that cleaves protein substrates at a highly specific position. They are involved in different aspects of the active cell death pathway. Most of them act through proteolytic degradations of cellular components. This paper describes the assay development, assay validation, and screening for inhibitors of this enzyme, which could be potential drug candidates. The assay uses homogeneous time-resolved fluorescence based on energy transfer from europium cryptate as donor to cross-linked allophycocyanin as acceptor (XL665). A double-tagged substrate, biotinyl-epsilon-aminocaproyl-L-aspartyl-L-glutamyl-L-valyl-Laspartyl-L-alanyl-L-propyl-N(epsilon)-(2,4-dinitrophenyl)-L-lysine-amide (biotin-X-DEVDAPK(dnp)-NH(2)), is conjugated with streptavidin cryptate and anti-dnp-XL665 monoclonal antibody. The close proximity between donor and acceptor induces a specific time-resolved fluorescence signal. In the presence of enzyme activity, the substrate cleavage induces an unlinking of the two fluorescent probes and, subsequently, the disappearance of the specific signal as a result of loss of proximity. Experiments to optimize the reagent concentration, incubation times, precision, reproducibility, and robustness are discussed in comparison with a fluorometric method.

Functional MR evaluation of temporal and frontal language dominance compared with the Wada test.

OBJECTIVE: To evaluate the reliability of temporal and frontal functional MRI (fMRI) activation for the assessment of language dominance, as compared with the Wada test. PATIENTS AND METHODS: Ten patients with temporal lobe epilepsy were studied using blood oxygen level dependent fMRI and echoplanar imaging (1.5-T). Three tasks were used: semantic verbal fluency, covert sentence repetition, and story listening. Data were analyzed using pixel by pixel autocorrelation and cross-correlation. fMRI laterality indices were defined for several regions of interest as the ratio (L - R)/(L + R), L being the number of activated voxels in the left hemisphere and R in the right hemisphere. Wada laterality indices were defined as the difference in the percentages of errors in language tests between left and right carotid injections. RESULTS: Semantic verbal fluency: The asymmetry of frontal activation was correlated with Wada laterality indices. The strongest correlation was observed in the precentral/middle frontal gyrus/inferior frontal sulcus area. Story listening: The asymmetry of frontal, but not temporal, activation was correlated with Wada laterality indices. Covert sentence repetition: No correlation was observed. CONCLUSIONS: There was a good congruence between hemispheric dominance for language as assessed with the Wada test and fMRI laterality indices in the frontal but not in the temporal lobes. The story listening and the covert sentence repetition tasks increased the sensitivity of detection of posterior language sites that may be useful for brain lesion surgery.

Mechanisms of virologic failure in previously untreated HIV-infected patients from a trial of induction-maintenance therapy. Trilège (Agence Nationale de Recherches sur le SIDA 072) Study Team).

CONTEXT: In the Trilège trial, following induction with a zidovudine, lamivudine, and indinavir regimen, human immunodeficiency virus (HIV) replication was less suppressed by 2-drug maintenance therapy than by triple-drug therapy. OBJECTIVE: To identify mechanisms of virologic failure in the 3 arms of the Trilège trial. DESIGN: Case-control study conducted from February to October 1998. SETTING: Three urban hospitals in Paris, France. PATIENTS: Fifty-eight case patients with virologic failure (HIV RNA rebound to >500 copies/mL in 2 consecutive samples) randomized to 3 therapy groups: triple drug (zidovudine, lamivudine, and indinavir), 8; zidovudine-lamivudine, 29; and zidovudine-indinavir, 21; the case patients were randomly matched with 58 control patients with sustained viral suppression. MAIN OUTCOME MEASURES: At virologic failure (S1 sample) and 6 weeks later (S2 sample), assessment of protease and reverse transcriptase gene mutations, plasma indinavir level, and degree of viral load rebound; pill count during induction and maintenance periods. RESULTS: Only 1 primary resistance mutation, M184V, was detected in S1 plasma samples from 4 of 6 patients in the triple-drug and in all 22 in the zidovudine-lamivudine therapy groups and in S2 plasma samples from 3 of 6 in the triple-drug and 20 of 21 in the zidovudine-lamivudine groups. Of controls, M184V was detected in 11 of 13 S1 plasma samples and in 10 of 11 S2 plasma samples. Indinavir levels were undetectable in all S1 samples but 2 in 7 triple-drug cases tested and in the expected range in 11 of 18 S1 and 5 of 12 S2 zidovudine-indinavir case plasma samples tested. Maintenance adherence rates were lower for cases vs controls for zidovudine (P = .05) and indinavir (P = .05). Low indinavir levels, lower adherence rates for zidovudine (P = .04) and lamivudine (P = .03), and rebound to near-baseline values suggested adherence as cause of early failure for 4 of 8 triple-drug cases. In the zidovudine-lamivudine arm, for which case and control adherence rates did not differ significantly (P = .96), most failures occurred late with low rebound, suggesting suboptimal drug potency. In the zidovudine-indinavir arm, virologic failures may be related to both mechanisms. CONCLUSIONS: During the maintenance phase early and late virologic failures appeared to be related more to problems of adherence and antiretroviral treatment potency, respectively, than to selection of resistant mutant viruses.

Mass screening programs for breast cancer in France--average values of assessment criteria.

Breast cancer is the most common cancer in women worldwide. Many studies have been performed worldwide to assess the effectiveness of screening in terms of reduced mortality due to breast cancer. Since the end of 1989, 10 breast cancer mass screening programs using mammography have been carried out in France under the sponsorship of the National Fund for Health Prevention, Education, and Information (FNPEIS) from the National Health Insurance of Salaried Workers (CNAMTS). These 10 campaigns, which are on a district scale, are organized according to variable methods and are assessed using a common procedure. Four groups of criteria are measured in this procedure, which investigates the impact, quality, effectiveness, and costs of screening programs. The average and extreme values of each criterion as calculated from the campaigns are presented in this paper. In order to enlighten the judgment on the French results, a comparison with the international standards in force and with the results of foreign screening programs is proposed.

Use of mammography as a breast cancer screening tool in six districts in France.

Mass screening programs to detect breast cancer are currently under way in many countries. In France, several districts have been running mammographic screening programs since 1989. A survey was conducted in five of these districts and in a sixth district where no screening program was implemented. Using a self-addressed questionnaire mailed to a sample of 1500 women aged over 20 years, the survey was aimed at assessing women's use of mammography as well as their knowledge and perception of mammographic breast cancer screening. According to district, the compliance of the women replying to the questionnaire ranged from 72 to 82%. The proportion of women who had at least one mammography during their life ranged from 41 to 54%, according to district. The percentage of women aged 50 to 69 who had one mammography within 3 years before the survey ranged from 57 to 78% in the experimental districts and was only 48% in the control district. In all districts, women did not know exactly at what age it is recommended to start screening and with what periodicity, but, when invited to do so, they were satisfied with the program and intended to participate again.

[Mass screening programs for breast cancer in France. Comparative evaluation]. / Les programmes de dépistage de masse du cancer du sein en France. Evaluation comparative.

OBJECTIVE: The purpose of this work was to comparatively assess the results of mass screening programs for breast cancer implemented in six French departments in 1986, within the scope of the National Fund for Health Prevention, Education and Information of the National Health Insurance Office of Salaried Workers. MATERIAL AND METHODS: The data collected by the screening centres were analyzed by ten assessment teams that were independent from the program promotion staff, all using the same evaluation form. A complementary population study performed in eight French districts then, allowed assessing the frequency of self-referred screening (mammography performed out of program). RESULTS: The rate of participation in screening programs, in relation to the invited population, ranged from 21 to 48%, according to the district (36% in average). This low participation was probably related to the extent of self-referred screening. In fact, 19 to 40% of women, according to the district, had previously had a screening mammographic coverage: rate was around 68% in women aged 50 to 69 years. Positive findings with mammography ranged from 4.5 to 15.8% (10.1% in average), while intervention rates ranged from 0.7 to 1.6% and detection rates from 3.8 to 6.2%. The ratio between benign tumors and cancers ranged from 0.7 to 2.1 according to the district. In order to enlighten the judgement on French results, we propose a comparison with the international standards in force. CONCLUSION: The various experiences with breast cancer screening in France show that this screening is technically feasible on the basis of existing medical structures. However, some criteria are still below the expected values, especially if compared with international standards. This result is probably accounted for by the high rate self-referred screening before age 40 in France. In these conditions, the question is whether extending breast cancer screening programs in France is an appropriate course of action.

Analysis of BCR/ABL transcripts in chronic myeloid patients by nested PCR using an immunoassay-like detection format.

We describe an 'immunoassay-like' detection format, based on the AMPLICIS technique for the routine detection of BCR/ABL transcripts in leukaemic patients. The AMPLICIS technique is characterized as a nested PCR coupled to solid phase isotopic or non-isotopic detection of PCR products. Comparison between this assay and a conventional PCR technique using Southern-blot analysis provided a good correlation between the two procedures. The assay, easier and faster than the conventional one, gives access to automation and therefore appears well suited for the routine screening of BCR/ABL chimaeric mRNAs.

[Lansoprazole versus ranitidine in the prevention of early recurrences of digestive hemorrhages from gastroduodenal ulcers. Randomized double-blind multicenter study]. / Lansoprazole versus ranitidine dans la prévention des récidives précoces des hémorragies digestives ulcéreuses gastro-duodénales. Etude multicentrique randomisée en double aveugle.

Strong inhibition of acid secretion could be able to decrease gastric and duodenal ulcer early rebleeding. OBJECTIVE--The aim of this double blind randomized trial was to compare early rebleeding rates of 2 groups of patients treated with ranitidine (600 mg/day) or lansoprazole (60 mg/day) per os for 6 consecutive days. METHODS--Seventy five patients with a high risk of rebleeding (clinical and endoscopical criteria) were included in this trial. These ulcers were Ia (n = 10), Ib (n = 20), IIa (n = 13), IIb (n = 32) in Forrest classification. RESULTS--Nineteen out of 75 patients rebled (25.3%): 11 out of 37 (30%) and 8 out of 38 (21%) in the ranitidine and lansoprazole groups respectively. Rates of rebleeding were 10%, 12.5%, 36% and 29% respectively in the ulcers grade Ia (previously treated with endoscopic sclerosis), Ib, IIa and IIb in the Forest classification. CONCLUSION--The rates of rebleeding were not statistically different in the 2 groups of treatment. The high rebleeding rates observed with Forrest IIa and IIb and duodenal ulcers support the need of haemostatic endoscopic therapy associated to antisecretory treatment in such patients.

[Experience in mass screening of breast cancer with mammography in France]. / Les expériences de dépistage de masse du cancer du sein par mammographie en France. Un protocole commun d'évaluation.

In the framework of the National Fund for Prevention, Health Education and Information, the setting-up in France, on an experimental basis, of mass breast cancer screening programs by mammography in ten departments leads to suggest a common protocol for the evaluation of these programs, before an eventual generalization to the whole country. These programs are based on common principles: local screening based on existing medical facilities, single view mammography with double reading. However, the screening organisation is different in each department according to the target population, the screening interval, the mode of invitation, the methods for arranging double reading, etc. The purpose of this article is to report on the work of the evaluation group of the ten programs, and to propose a methodology for comparing the screening experiences in order to measure the role of the organisation methods. It gives definitions and modes of calculations for the evaluation criteria in four fields: impact, quality, efficacy and cost (with details about the feasibility of data collection) and proposes a reflection on analysis techniques in order to develop an optimum mass screening strategy.

Fast solid support detection of human papillomavirus in in vitro amplified DNA using a DNP-anti DNP monoclonal antibody couple.

In some anogenital lesions the detection of certain types of human papilloma virus, especially oncogenic types, is of interest. In a first step during a prospective study, we compared two methods for the detection of human papillomavirus (HPV) DNA in clinical samples: Southern blotting followed by hybridization with a cloned radioactive genomic probe and a classical polymerase chain reaction (PCR) followed by hybridization with a 32P-labelled oligonucleotide probe. 118 biopsies and swabs were examined for HPV 6/11, 16, 18 and 33, 67 positive reactions were found by both methods, 5 positives only by PCR and 2 positives only by Southern blot for unidentified HPV. Patients with anogenital condylomas, dysplasias and carcinomas or asymptomatic patients were studied. Most high grade (II and III) dysplasias were associated with HPV 16 and HPV 18. Condylomata lesions and low grade dysplasia (grade I) were associated mostly with HPV 6/11, mixed type of HPV, less frequently with HPV 16 or HPV 18. As a second step a nested PCR coupled to solid support detection method was used as described by Sauvaigo et al. (1990) Nucleic Acids Res. 18, 3175-3183) to study a panel of 30 previously qualified different HPV DNA extracts. In this procedure the second round of PCR amplification involves biotinylated and dinitrophenylated labelled primers allowing the capture of PCR amplified HPV DNA sequences on streptavidin coated tubes and its revelation. We describe an improvement of HPV DNA detection by means of single-step immunoenzymatic revelation involving anti-DNP monoclonal antibodies conjugated to horseradish peroxidase enzyme. A perfect correlation with the previous results was obtained. This solid support method allows a faster and easier HPV typing compared to methods using membrane transfer.

Effect of nomegestrol acetate, a new 19-nor-progesterone derivative, on pituitary-ovarian function in women.

After two control cycles, 13 normally menstruating women were treated from day 5 to 25 of the third consecutive cycle with nomegestrol acetate (NOM Ac) 1.25, 2.5 or 5 mg once a day. Plasma oestradiol, FSH and LH concentrations were assayed daily from day 5 to day 25 and plasma progesterone concentrations from day 12 to day 25. Ovulation was inhibited in every woman; LH and progesterone levels were uniformly depressed. With 5 and 2.5 mg/day, plasma oestradiol remained low with high FSH values. With 1.25 mg/day, oestradiol concentrations reached levels similar to those achieved during the control follicular phase, with a concomitant decrease in FSH secretion. These results show an hypothalamic-pituitary effect and suggest an ovarian action, both responsible for a potentially useful contraceptive property.