Synthesis, conformation and antiproliferative activity of isothiazoloisoxazole 1,1-dioxides.

Sixteen new isothiazoloisoxazole 1,1-dioxides, one new isothiazolotriazole and one new isothiazolopyrazole have been synthesised by using 1,3-dipolar cycloadditions to isothiazole 1,1-dioxides. One sub-set of these isothiazoloisoxazoles showed low µM activity against a human breast carcinoma cell line, whilst a second sub-set plus the isothiazolotriazole demonstrated an interesting restricted rotation of sterically hindered bridgehead substituents. A thiazete 1,1-dioxide produced from one of the isothiazole 1,1-dioxides underwent conversion into an unknown 1,2,3-oxathiazolin-2-oxide upon treatment with Lewis acids, but was inert towards 1,3-dipoles and cyclopropenones. Six supporting crystal structures are included.

[Comparative norms of RAPID neuropsychological battery tests for subjects aged between 50 and 89 years]. / Normes comparatives de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 50 à 89 ans.

INTRODUCTION: RAPID, a battery of rapid neuropsychological tests, includes neuropsychological tests calibrated for different populations according to diverse methodologies. This makes the comparison and interpretation of the results difficult. The aim of this study was to build comparative norms for the RAPID battery using a single methodology in a unique population. POPULATION AND METHODS: The RAPID Battery includes nine different tests: the Memory Impairment Screen, the Isaacs Set Test, the Mini-Mental State Examination, the Free and Cued Recall Test, the Trail Making Test, a test for copying geometric figures as part of the BEC 96, a test for verbally naming images and a test for matching categories. A cohort of 476 subjects aged 50 to 89 were randomly selected from the medical records of 11 practitioners. RESULTS: The norms were stratified according to age (50-59, 60-69, 70-79 and 80-89 years) and education level of the subjects. The first level includes subjects with the French Primary Education Certificate or lower. The second level includes subjects with the Certificate of Professional Aptitude or the Brevet (equivalent to the GCSE). The third level includes subjects with the Baccalaureate or higher. Given that most of the tests did not satisfy the normal distribution, percentiles (tenth, twenty-fifth, seventy-fifth, ninetieth percentile and median) were used to define age and education norms. The results show a high participation rate (75 %) and are similar to those obtained in the literature: The results decreased with age and improved in grade level. Nevertheless, the results exhibited great variability for the tenth percentile in comparison with results reported in the literature. CONCLUSION: The development of comparative norms for the RAPID battery from a same sample facilitates the interpretation of individual results in terms of cognitive profile.

[Quality of life after corneal transplantation: a retrospective study]. / Qualité de vie après greffe de cornée: étude rétrospective.

PURPOSE: To assess how clinical and social characteristics influence health-related quality of life among patients who have undergone corneal transplantation. METHODS: Sixty-eight patients followed up for at least 1 year after corneal transplantation participated in this study. Data were collected on social status, systemic co-morbidities, ocular history, best corrected visual acuity, and a detailed ocular examination. Questionnaires that allowed calculation of VF14 and the SF36 scores were filled out for each participant interview. The associations between questionnaire outcomes and social status, ophthalmic status, and general health were evaluated using one-way analysis of variance and multiple stepwise linear regression. RESULTS: The mean best-corrected visual acuity (BCVA) was significantly better in the operated eye for keratoconus and dystrophies than for bullous keratopathy. There is a strong relationship between BCVA in the operated eye and the VF14 score (beta=8.45, p=0.005) and also between BCVA of the contralateral eye and the VF14 score (beta=19.91, p<0.0001). Correlations between VF14 and SF36 were all positive (range r=0.29-0.49, p<0.01). CONCLUSION: This retrospective analysis provided strong evidence for the validity and reliability of the VF14 as an instrument for testing visual disabilities or satisfaction in patients who had corneal transplantation. Astigmatism or anisometropia did not affect VF14 and SF36 scores. The most important factors associated with the VF14 score and SF36 measures were the visual acuity of the operated eye as well as the contralateral one, including their physical function, vitality, and the patient's perception of mental and general health.

Cigar, pipe, and cigarette smoking and bladder cancer risk in European men.

OBJECTIVE: Estimating the risk of bladder cancer from cigar and pipe smoking is complicated by a small number of non-cigarette smokers included in most relevant studies. METHODS: We undertook a pooled analysis of the data on men from six published case-control studies from Denmark, France, Germany, and Spain, to assess the association between pipe and cigar smoking and bladder cancer, and to compare it with the risk from cigarette smoking. Complete history of tobacco smoking was ascertained separately for cigarettes, cigars, and pipe. Odds ratios (ORs) were estimated after adjusting for age, study, and employment in high-risk occupations. RESULTS: The pooled data set comprised 2279 cases and 5268 controls, of whom 88 cases and 253 controls smoked only cigars or pipe. The OR for pure cigarette smoking was 3.5 (95% confidence interval [CI] 2.9-4.2), that for pure pipe smoking was 1.9 (95% CI 1.2-3.1) and that for pure cigar smoking was 2.3 (95% CI 1.6-3.5). The increase in the OR of bladder cancer that was observed with duration of smoking was non-significantly lower for cigars than for cigarettes. CONCLUSION: Our results suggest that smoking of cigars and pipe is carcinogenic to the urinary bladder, although the potency might be lower than for cigarettes.

Genetic polymorphism at the glutathione S-transferase (GST) P1 locus is a breast cancer risk modifier.

The isolation of full-length cDNAs of naturally occurring GSTP1 gene variants, and the demonstration that these alleles are distributed in the normal population, have provided conclusive evidence that the human GSTP1 gene locus is polymorphic and that specific GSTP1 alleles may be associated with different risk for cancers or other diseases. Recent data have indicated that the different GSTP1 alleles encode proteins with different enzymatic activities against carcinogens. In this case-control study, we examined the effect of the GSTP1 genetic polymorphism and its interaction with other factors to determine breast cancer risk. GSTP1 and GSTM1 genotypes of 220 breast cancer patients and 196 controls, all residents of western France, were examined. Data on menopausal status and family cancer history were obtained from 195 patients and 147 controls. Exons 5 and 6 of the GSTP1 gene, which contain the polymorphic nucleotide transitions, were analyzed by DNA polymerase chain reaction-restriction fragment length polymorphism to distinguish between the GSTP1 alleles. In the control population, GSTP1 allelic frequencies were 64.3%, 26.0% and 9.7%, respectively, for GSTP1*A, GSTP1*B and GSTP1*C. In the breast cancer patients, the frequencies were 67.9% for GSTP1*A, 26.8% for GSTP1*B and 5.3% for GSTP1*C. In multivariate analysis, breast cancer risk increased by 7.7-fold (p < 0.001) in women with a family history of cancers and 2.18-fold (p = 0.026) in non-GSTP1*C individuals. GSTM1 genotypes did not emerge as risk factor. Our results show that in addition to well-known risk factors, in particular, a family history of cancer, GSTP1 allelopolymorphism is a significant modifier of breast cancer risk. The results also suggest a protective role against breast cancer for the GSTP1*C allele.

[Trends for the management of pancreatic adenocarcinoma in a hospitalized-based population (1980-1994)]. / Evolution de la prise en charge de l'adénocarcinome pancréatique dans une série hospitalière (1980-1994).

OBJECTIVE: To determine the trends for the management of pancreatic adenocarcinoma between 1980 and 1994 in a hospital-based population. METHODS: Data of patients from the Doubs department and hospitalized for pancreatic adenocarcinoma in the University Hospital of Besançon were analyzed. Two study periods were determined: 1980-1989 and 1990-1994. RESULTS: One hundred and thirty five cases were diagnosed (77 male, 58 female, mean age 65.6 +/- 12.1 years). Weight loss (62.3%), pain (52.7%) and jaundice (43.3%) were the most frequently reported symptoms. Their proportion and their duration were similar according to the period. Diagnosis of the pancreatic tumor was made by ultrasonography or tomodensitometry in 97.8% patients. Distribution of tumors according to the AJCC staging was unchanged during the study. Pre-operative screening frequently underestimated tumor stage, even in the more recent period. The rate of complete resection (18.5%) did not increase. The 5-year actuarial survival rate (3.05%) remained unchanged. A metastatic spread represented the only independent prognostic factor. CONCLUSIONS: The management and the prognosis of pancreatic adenocarcinoma have not fundamentally changed. Recent imaging techniques should improve staging accuracy. Advances in adjuvant therapies represent a major issue for the future.

Relative survival analysis of 252 patients with COPD receiving long-term oxygen therapy.

OBJECTIVES: A survival analysis was conducted on patients with COPD receiving long-term oxygen therapy (LTOT) to compare two different statistical methods. METHODS: We used a multivariate crude (observed) survival model (Cox) and a multivariate relative survival model (Hakulinen). Only the latter is able to correct the survival by adjusting it to the normal life expectancy of the studied patients. PATIENTS: Two hundred fifty-two hypoxemic COPD patients (207 male) requiring LTOT were included. Mean PaO2 was <50 mm Hg before oxygen therapy. Mean age was >69 years (SE: 9.9). They had severe bronchial obstruction: mean FEV1 was <33% (10.6) of predicted values, with some CO2 retention: mean PaCO2 was 45.6 (7.1) mm Hg. By December 31, 1995, 189 patients had died (75%) and 13 (5%) were unavailable for follow-up. RESULTS: The overall crude survival was poor: 80.9% after 1 year, 67.1% after 2 years, 34.7% after 5 years, and 7.1% after 10 years. In the crude multivariate analysis (Cox), the negative prognostic factors were age and hypercapnia. The overall relative survival (Hakulinen), corrected for life expectancy, was 82.8% after 1 year, 70.8% after 2 years, 41.5% after 5 years, and 10.25% after 10 years. In the final multivariate relative model, age was no longer significant and the only bad prognostic factor was hypercapnia with a relative risk of 1.97 (1.16 to 3.34). CONCLUSION: This work shows the inadequacy of the Cox observed survival model when it comes to appreciating the real prognostic impact of age, because of the confusing factor associated with a normal life expectancy.

Brain cancer mortality among French farmers: the vineyard pesticide hypothesis.

In this study, the authors assessed the contribution of vineyard pesticides to brain cancer mortality among agricultural workers. A pesticide exposure index (PEI) in vineyards was calculated for 89 French geographical units (départements). The authors estimated standardized mortality ratios among male farmers and farm laborers aged 35-74 y for the years 1984-1986. Poisson regression models, which were fitted to the ecological data, included random effects. Mortality from brain cancer among farmers was significantly higher than mortality for the overall population (standardized mortality ratio = 1.25, p < .001). Univariate analysis revealed a significant link with pesticide exposure in vineyards (relative risk = 1.10; 95% confidence interval = 1.03, 1.18), as did multivariate analysis (relative risk = 1.11; 95% confidence interval = 1.03, 1.19). These results corraborate the evidence that pesticides in vineyards contribute to mortality from brain cancer among farmers.

Some methods to address collinearity among pollutants in epidemiological time series.

The aim of this paper is to provide accurate estimation methods for regression models used in epidemiological time series to deduce quantitative morbidity relationships. Such models often include highly correlated variables (pollutant levels and climatic conditions) as well as lagged and unlagged values of the same variables (which also show a high collinearity due to the stochastic dependency of consecutive measurements). We first describe some methods to detect and assess multicollinearity. We recall the drawbacks of usual methods of estimation, and then after briefly mentioning traditional solutions, we explore three alternative methods accounting for multicollinearity: Sclove's estimation; Almon's method; and a combination of Almon's method and principal components procedure. We compare these methods in obtaining efficient estimators on environmental epidemiological data (children's hospital admissions as dependent variable and unlagged and lagged values of outdoor temperature, SO2, NO and CO as explanatory variables.