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1.  Occupational risk factors have to be considered in the definition of high-risk lung cancer populations 
British Journal of Cancer  2012;106(7):1346-1352.
The aim of this study was to compute attributable fractions (AF) to occupational factors in an area in North-Eastern France with high lung cancer rates and a past of mining and steel industry.
A population-based case–control study among males aged 40–79 was conducted, including confirmed primary lung cancer cases from all hospitals of the study region. Controls were stratified by broad age-classes, district and socioeconomic classes. Detailed occupational and personal risk factors were obtained in face-to-face interviews. Cumulative occupational exposure indices were obtained from the questionnaires. Attributable fractions were computed from multiple unconditional logistic regression models.
A total of 246 cases and 531 controls were included. The odds ratios (ORs) adjusted on cumulative smoking and family history of lung cancer increased significantly with the cumulative exposure indices to asbestos, polycyclic aromatic hydrocarbons and crystalline silica, and with exposure to diesel motor exhaust. The AF for occupational factors exceeded 50%, the most important contributor being crystalline silica and asbestos.
These AFs are higher than most published figures. This can be because of the highly industrialised area or methods for exposure assessments. Occupational factors are important risk factors and should not be forgotten when defining high-risk lung cancer populations.
PMCID: PMC3314791  PMID: 22453127
lung cancer; case–control; occupational; attributable fractions
2.  Prognostic relevance of P‐cadherin expression in melanocytic skin tumours analysed by high‐throughput tissue microarrays 
Journal of Clinical Pathology  2006;59(7):699-705.
To investigate whether protein expression or cellular localisation of P‐cadherin is associated with clinicopathological characteristics in benign and malignant melanocytic skin tumours.
Experimental design
P‐cadherin expression and the Ki‐67 labelling index were analysed immunohistochemically by using tissue microarrays (TMAs). Membranous and cytoplasmic expression was scored semiquantitatively (0 to 2+).
P‐cadherin protein expression of any intensity (1+ to 2+) was detected in the membrane in 41.5% (132/318) and in the cytoplasm in 64.2% (204/318) of patients. In general, P‐cadherin expression was significantly reduced in malignant melanomas (p<0.001) and melanoma metastases (p<0.001), compared with benign nevi. Additionally, loss of membranous P‐cadherin was associated with Clark level (p = 0.011) and tumour thickness (p<0.001). Interestingly, a significantly lower P‐cadherin expression was shown by dermal nevi than by compound and junctional nevi (p = 0.005; p = 0.025). In primary melanomas, a Ki‐67 labelling index <5% was not associated with P‐cadherin protein expression, suggesting that loss of P‐cadherin expression was not associated with proliferation. None of the other clinical and histological factors analysed was significantly related to P‐cadherin expression. Low cytoplasmic P‐cadherin expression was associated with tumour recurrence (p = 0.03) in all the patients who were analysed. After testing various multivariate Cox regression models, loss of cytoplasmic P‐cadherin expression remained a highly significant adverse risk factor for tumour recurrence in patients with tumours <2 mm.
Loss of cytoplasmic P‐cadherin expression is common in advanced melanomas and can be a prognostic marker of progression in patients with melanoma, most useful in patients with primary tumours <2 mm in thickness.
PMCID: PMC1860409  PMID: 16565225
3.  Mortality among Paris sewage workers 
To describe the mortality of Paris sewage workers.
A cohort of all Paris sewage workers since 1970 was established and followed up in mortality until 1999. The causes of death were determined by matching with a national database. The mortality rates were compared to the rates of a local reference population.
A large excess in mortality (standardised mortality ratio (SMR) = 1.25; 530 cases, 95% CI 1.15 to 1.36) and in particular mortality from cancer (SMR = 1.37, 235 cases) was detected which was particularly important in the subgroup of subjects who had left employment because they resigned or were laid off (SMR = 1.77; 50 cases). The excess mortality is to a large extent due to alcohol related diseases (SMR = 1.65, 122 cases) especially malignant (SMR = 1.85, 16 cases) and non‐malignant (SMR =  1.68, 38 cases) liver diseases, lung cancer (SMR = 1.47, 68 cases), and infectious diseases (SMR =  1.86, 25 cases). The SMRs for some diseases (all cancers, cancers of the oesophagus and lung, all alcohol related diseases) seem to increase with duration of employment as a sewage worker. Other than lung cancer, smoking related diseases were not in excess.
The increased mortality by both malignant and non‐malignant liver diseases is probably due to excessive alcohol consumption, but could be partially the result of occupational exposure to chemical and infectious agents and interactions of these factors. The excess lung cancer is unlikely to be due to an increased smoking prevalence.
PMCID: PMC2078140  PMID: 16497857
mortality; sewage workers; cancer; chronic liver diseases; epidemiology
4.  Lung cancer risk and talc not containing asbestiform fibres: a review of the epidemiological evidence 
A literature search was done and all epidemiological cancer studies mentioning talc as a risk factor were selected. The talc exposed populations were divided into three groups: (1) populations in which no other occupational carcinogen was mentioned (only talc millers satisfied this criterion); (2) populations of talc miners exposed to talc, quartz, and/or radon; and (3) other industrial populations in which talc is associated with quartz, nitrosamines, and asbestos depending on the study. No excess lung cancer mortality was found for the populations of talc millers exposed to high levels of talc but without any other potential carcinogen (SMR = 0.92, 42 cases) while the summary of mortality of talc miners exposed to quartz and/or radon was in excess (fixed effect SMR = 1.20, random effect RR = 1.85, 40 cases). Six studies in other industrial settings were identified. All reported increased lung cancer mortality among talc exposed workers but the talc exposure was confounded with other carcinogens and only one study was able to adjust on them. In conclusion, no increased lung cancer mortality was observed among talc millers despite their high exposure experience. In populations in which talc was associated with other potential carcinogens, some lung cancer excesses were observed.
PMCID: PMC2078026  PMID: 16361399
talc; lung cancer; literature review
5.  Morphological characterisation of Crohn’s disease fistulae 
Gut  2004;53(9):1314-1321.
Background: Fistulae are a common complication in up to 35% of all patients with Crohn’s disease. Their therapy is difficult and frequently unsatisfactory. To date, no histological comparison of Crohn’s disease fistulae with non-inflammatory bowel disease fistulae has been performed. In addition, Crohn’s disease fistulae have not been well characterised morphologically.
Methods: Eighty four fistulae from Crohn’s disease patients were compared with 13 fistulae from controls. Haematoxylin-eosin staining, electron microscopy, and immunohistochemistry for panCytokeratin (epithelial cells), CD20 (B cells), CD45R0 (T cells), and CD68 (macrophages) were performed according to standard techniques. In addition, histopathological findings were compared with clinical and laboratory data.
Results: In 31.0% of controls and 27.4% of Crohn’s disease specimens, fistulae had a lining of flattened intestinal epithelium without goblet cells or, in the case of cutaneous/perianal disease, narrow squamous epithelium. Non-epithelialised fistulae were covered by a thin layer of (myo)fibroblasts, focally forming a new basement membrane, as demonstrated by electron microscopy. All fistulae were surrounded by granulation tissue. Crohn’s disease fistulae presented with central infiltration by CD45R0+ T cells, followed by a small band of CD68+ macrophages and dense accumulation of CD20+ B cells. In contrast, in controls, there was dense infiltration by CD68+ macrophages with only few CD20+ B cells and CD45R0+ T lymphocytes.
Conclusions: Fistulae in Crohn’s disease differ markedly from non-Crohn’s disease fistulae with regard to their cellular composition. The presence of an epithelial lining in a subgroup of fistulae may be important for the therapeutic approach and healing process.
PMCID: PMC1774207  PMID: 15306592
Crohn’s disease; fistulae; histology; immunohistochemistry; electron microscopy
6.  Asbestos fibreyears and lung cancer: a two phase case–control study with expert exposure assessment 
Aims: To assess the cumulative effect of asbestos on lung cancer risk where the exposure is assessed by an expert rating.
Methods: 1678 male cases and controls were enrolled in a population based matched case–control study, focused on occupational risk factors, carried out in West Germany. The exposure to asbestos was computed as lifelong working hours. For a validation subsample of 164 matched pairs from this study the intensity of asbestos exposure was further assessed by a panel of experts in order to obtain an estimate of the cumulative exposure on a time by intensity scale (fibreyears). The information on duration of asbestos exposure in the original study was combined with the fibreyears following the two phase case control study paradigm.
Results: The number of exposed subjects in the validation subsample was 75 cases and 71 controls. The percentage of subjects with a cumulative exposure ≤1, 1 to ≤10, and >10 fibreyears was 16%, 15%, and 15% for the cases and 18%, 16%, and 9% respectively for the controls. The smoking adjusted odds ratios for the fibreyears based on an unconditional logistic regression were 0.81, 1.02, and 1.60 respectively with increasing exposure categories (not significant). The coefficient (beta) for a log transformed trend was 1.156. Applying the two phase paradigm, these odds ratios became 0.86, 1.33, and 1.94; the latter reached significance and the beta coefficient was 1.178.
Conclusions: The two phase paradigm allowed us to obtain a more precise estimate of the effect of asbestos on lung cancer. Results are consistent with a doubling of the lung cancer risk with 25 fibreyears asbestos exposure.
PMCID: PMC1740301  PMID: 12040118
7.  A cohort mortality and nested case-control study of French and Austrian talc workers 
Objectives: To study whether the mortality from non-malignant and malignant respiratory diseases of workers employed in French and Austrian talc mines and mills is related to their long term occupational exposure.
Methods: Two historical cohorts were set up comprising all male subjects who had been working continuously for at least 1 year in a series of talc producing companies in France and Austria. The French cohort consisted of those employed at a site in the French Pyrenees and working between 1 January 1945 and 31 December 1994. The Austrian cohort consisted of the workers employed between 1 January 1972 and 31 December 1995 in one of four industrial sites in the Austrian Alps. The mortality within the cohorts was compared with local death rates. Two nested case-control studies focusing on non-malignant and malignant respiratory diseases were set up to estimate possible dose-response relations with cumulative exposure to talc dust based on an industry specific job exposure matrix.
Results: Mortality from lung cancer was in small excess in both cohorts (France, standardised mortality ratio (SMR) 1.23, 21 cases observed, 95% confidence interval (95% CI) 0.76 to 1.89; Austria, SMR 1.06, seven observed, 95% CI 0.43 to 2.19). A non-significant excess mortality was found for all non-malignant respiratory diseases in the French cohort due to a significant excess for pneumoconiosis (SMR 5.56, three observed, 95% CI 1.12 to 16.2). The case-control study of non-malignant respiratory disease showed an increased mortality in the highest exposure groups (odds ratio (OR) 2.5 for a cumulative exposure ≥800 with a significant trend (OR/100 1.08) with cumulative exposure to talc. On the contrary, no increasing trend could be found in the case-control study of lung cancer. This result must be interpreted considering the small cohort size. Adjustment on smoking and exposure to quartz did not influence these results to any extent.
Conclusions: The mortality from non-malignant respiratory disease was found to be related to high cumulative exposure to talc dust. The small excess in lung cancer does not seem to be attributable to talc.
PMCID: PMC1740253  PMID: 11850552
8.  An epidemiological study of the respiratory health of workers in the European refractory ceramic fibre industry 
OBJECTIVES—To investigate possible relations between respiratory health and past airborne exposure to refractory ceramic fibres (RCFs) and respirable dust in workers at six European factories, studied previously in 1987.
METHODS—The target population comprised all current workers associated with RCF production, plus others who had participated in 1987 "leavers". Information was collected on personal characteristics, chest radiographs, lung function, respiratory symptoms, smoking, and full occupational history. Regression analysis was used to study relations between indices of health of individual workers and of cumulative exposure to airborne dust and fibres, and likely past exposure to asbestos. 
RESULTS AND DISCUSSION—774 workers participated (90% of current workers, 37% of leavers). Profusion of small opacities in exposed workers (51% 0/1+; 8% 1/0+) was similar to that among an unexposed control group but higher than in new readings of the 1987 study films (11% 0/1+, 2% 1/0+). The large difference between 1987 and recent films may be, at least in part, a reading artefact associated with film appearance. Small opacities of International Labour Organisation (ILO) category 1/0+ were not associated with exposure. An association of borderline significance overall between 0/1+ opacities and exposure to respirable fibres was found for some exposure periods only, the time related pattern being biologically implausible. Pleural changes were related to age and exposure to asbestos, and findings were consistent with an effect of time since first exposure to RCFs. Among men, forced expired volume in 1 second (FEV1) and forced vital capacity (FVC) were inversely related to exposure to fibres, in current smokers only. FEV1/ FVC ratio and transfer factor (TLCO) were not related to exposures. The estimated restrictive effect was on average mild. Prevalence of respiratory symptoms was low. Chronic bronchitis and its associated symptoms (cough, phlegm) showed some association with recent exposure to respirable fibres. This could be due to an irritant effect of RCFs.

Keywords: respiratory health; ceramic fibres
PMCID: PMC1740079  PMID: 11706147
9.  Immunological evaluation of the new stable ultrasound contrast agent LK565: a phase one clinical trial 
Ultrasound contrast agents (UCAs) allow the enhancement of vascular definition, thereby providing more diagnostic information. LK565 is a new second-generation UCA based on synthetic polymers of aspartic acid which is eliminated from the blood stream via phagocytosis. LK565 forms very stable air-filled microspheres and is capable of repeated passage through the pulmonary capillary bed after peripheral intravenous injection. This characteristic allows examination of the cardiac function or extracardiac vessel abnormalities up to 15 minutes.
A phase one clinical study was conducted on 15 healthy volunteers to identify the development of an undesirable immune response. Phagocytosis capacity, TNF-α secretion, and MHC class II upregulation of monocytes was monitored, as well as microsphere specific antibody development (IgM, IgG). Furthermore, the kinetics of the activation surface markers CD69, CD25, CD71, and CD11b on leukocytes were analyzed.
Due to LK565-metabolism the administration of the UCA led to saturation of phagocytes which was reversible after 24 hrs. Compared to positive controls neither significant TNF-α elevation, neither MHC class II and activation surface markers upregulation, nor specific antibody development was detectable.
The administration of LK565 provides a comfortable duration of signal enhancement, esp. in echocardiography, without causing a major activation cascade or triggering an adaptive immune response. To minimize the risk of undesirable adverse events such as anaphylactoid reactions, immunological studies should be included in clinical trials for new UCAs. The use of LK565 as another new ultrasound contrast agent should be encouraged as a safe means to provide additional diagnostic information.
PMCID: PMC520823  PMID: 15357870
10.  Alterations in p53 predict response to preoperative high dose chemotherapy in patients with gastric cancer 
Molecular Pathology  2003;56(5):286-292.
Aims: To evaluate the usefulness of molecular markers in predicting histopathological and clinical response to preoperative high dose chemotherapy (HDCT) and survival of patients with advanced gastric cancer.
Methods: In a phase II trial, 25 patients with metastatic gastric cancer received preoperative tandem HDCT consisting of etoposide, cisplatin, and mitomycin, followed by autologous bone marrow transplantation to achieve surgical resectability. Samples before and after treatment, from normal and tumour tissue, were characterised histopathologically, and both p53 and BAX expression was analysed by immunohistochemistry. Pretreatment formalin fixed, paraffin wax embedded samples from normal and tumour tissue were microdissected, and the extracted DNA was preamplified using improved primer extension preamplification polymerase chain reaction. Detection of microsatellite instability (MSI) or loss of heterozygosity (LOH) was performed using markers for p53, BAX, BAT25, BAT26, D2S123, D17S250, and APC. Exons 5–9 of the p53 gene were sequenced directly on ABI 373.
Results: Four parameters were significantly associated with response to chemotherapy and prolonged overall survival: positive p53 immunostaining, positive p53 mutation status before chemotherapy, strong histological regression induced by preoperative HDCT, and surgical treatment. Patients’s sex or age, tumour location or stage, lymph node status, Lauren classification, MSI, or LOH did not influence duration of survival significantly in this high risk population.
Conclusion: Positive p53 immunostaining and p53 mutation status in pretreatment tumour biopsies might be useful molecular predictors of response and prognosis in patients with advanced gastric cancer treated by preoperative HDCT.
PMCID: PMC1187340  PMID: 14514923
gastric cancer; preoperative high dose chemotherapy; molecular parameters; histological regression; p53
11.  Lung cancer mortality in a site producing hard metals 
OBJECTIVES—To study the mortality from lung cancer from exposures to hard metal dust at an industrial site producing hard metals—pseudoalloys of cobalt and tungsten carbide—and other metallurgical products many of which contain cobalt.
METHODS—A historical cohort was set up of all subjects who had worked for at least 3 months on the site since its opening date in the late 1940s. A full job history could be obtained for 95% of the subjects. The cohort was followed up from January 1968 to December 1992. The exposure was assessed by an industry specific job exposure matrix (JEM) characterising exposure to hard metal dust from 1 to 9 and other possibly carcinogenic exposures as present or absent. Smoking information was obtained by interview of former workers. Standard lifetable methods and Poisson regression were used for the statistical analysis of the data.
RESULTS—Mortality from all causes was close to the expected (standardised mortality ratio (SMR) 1.02, 399 deaths) whereas mortality from lung cancer was significantly increased among men (SMR 1.70; 46 deaths, 95% confidence interval (95% CI) 1.24 to 2.26). By workshop, lung cancer mortality was significantly higher than expected in hard metal production before sintering (SMR 2.42; nine deaths; 95%CI 1.10 to 4.59) and among maintenance workers (SMR 2.56; 11 deaths; 95%CI 1.28 to 4.59), whereas after sintering the SMR was lower (SMR 1.28; five deaths; 95%CI 0.41 to 2.98). The SMR for all exposures to hard metal dust at a level >1 in the JEM was in significant excess (SMR 2.02; 26 deaths; 95%CI 1.32 to 2.96). The risks increased with exposure scores, duration of exposure, and cumulative dose reaching significance for duration of exposure to hard metal dust before sintering, after adjustment for smoking and known or suspected carcinogens.
CONCLUSION—Excess mortality from lung cancer was found among hard metal production workers which cannot be attributed to smoking alone. This excess occurred mostly in subjects exposed to unsintered hard metal dust.

Keywords: lung cancer; hard metals
PMCID: PMC1739997  PMID: 10896965
12.  Symptoms, airway responsiveness, and exposure to dust in beech and oak wood workers 
OBJECTIVES—To investigate the relation between levels of cumulative exposure to wood dust and respiratory symptoms and the occurrence of bronchial hyperresponsiveness among beech and oak workers.
METHODS—114 Male woodworkers from five furniture factories and 13 male unexposed controls were examined. The unexposed control group was supplemented by 200 male historical controls. Statistical analyses were performed excluding and including the historical controls. Dust concentration was measured by personal sampling methods. Cumulative exposure to dust was calculated for each woodworker by multiplying the duration of the work by the intensity of exposure ( Bronchial hyperresponsiveness was assessed by the methacholine bronchial challenge test. Subjects were labelled methacholine bronchial challenge positive if forced expiratory volume in 1 second (FEV1) fell by ⩾20%. The linear dose-response slope was calculated as the last dose divided by the total dose given.
RESULTS—443 Dust samples were collected. The median cumulative exposure to dust was 110 with lower and upper quartiles at 70 and 160 Overall, no declines in FEV1 and forced vital capacity (FVC) were found with increasing exposures. A dose-response relation was found between intensity of exposure on the one hand, and sore throat, increased prevalence of positive methacholine bronchial challenge tests, and steeper dose-response slope, on the other.
CONCLUSION—Exposure to oak and beech dust may lead to the development of sore throat and bronchial hyperresponsiveness.

Keywords: bronchial hyperresponsiveness; wood dust; beech; oak
PMCID: PMC1739936  PMID: 10810114
13.  Respiratory symptoms and bronchial responsiveness in lifeguards exposed to nitrogen trichloride in indoor swimming pools 
OBJECTIVES: To measure the levels of exposure to nitrogen trichloride (NCl3) in the atmosphere of indoor swimming pools and to examine how they relate to irritant and chronic respiratory symptoms, indices of pulmonary function, and bronchial hyperresponsiveness to methacholine in lifeguards working in the pools. METHOD: 334 lifeguards (256 men; 78 women) recruited from 46 public swimming pools (n = 228) and 17 leisure centre swimming pools (n = 106) were examined. Concentrations of NCl3 were measured with area samplers. Symptoms were assessed by questionnaire and methacholine bronchial challenge (MBC) test by an abbreviated method. Subjects were labelled MBC+ if forced expiratory volume in one second (FEV1) fell by > or = 20%. The linear dose- response slope was calculated as the percentage fall in FEV1 at the last dose divided by the total dose given. RESULTS: 1262 samples were taken in the 63 pools. Mean NCl3 concentrations were greater in leisure than in public pools. A significant concentration-response relation was found between irritant eye, nasal, and throat symptoms-but not chronic respiratory symptoms-and exposure concentrations. Among women, the prevalence of MBC+ was twice as great as in men. Overall, no relation was found between bronchial hyperresponsiveness and exposure. CONCLUSIONS: The data show that lifeguards exposed to NCl3 in indoor swimming pools are at risk of developing irritant eye, nasal, and throat symptoms. Exposure to NCl3 does not seem to carry the risk of developing permanent bronchial hyperresponsiveness, but this association might have been influenced by self selection. The possibility that subjects exposed to NCl3 are at risk of developing transient bronchial hyperresponsiveness cannot be confidently ruled out.
PMCID: PMC1757567  PMID: 9624280
14.  Airway responsiveness, respiratory symptoms, and exposures to soluble oil mist in mechanical workers. 
OBJECTIVES: To assess the relation between measured levels of exposure to soluble oil mists in a plant manufacturing ball bearings, and both respiratory symptoms and airway responsiveness in the workforce. METHODS: 114 male workers exposed to oil mist and 55 unexposed male controls from nearby factories were studied. Soluble oil mist concentrations were measured with area samplers. Respiratory symptoms were assessed by questionnaire and measurement of airway responsiveness to methacholine with an abbreviated method. Subjects were labelled positive to methacholine airway challenge (MAC+) if forced expiratory volume in one second (FEV1) fell by > or = 20%. The linear dose-response slope was calculated as the percentage fall in FEV1 at the last dose divided by the total dose given. RESULTS: Geometric mean concentrations of oil mists ranged from 0.65 mg/m3 (GSD 1.29) to 2.20 mg/m3 (GSD 1.55) based on 92 measurements obtained from 1979-93. The prevalence of chronic cough or phlegm, bouts of bronchitis, and dyspnoea was greater among exposed workers than among controls (odds ratio (OR) 4.64, P = 0.002 for chronic cough and phlegm). After adjustment for smoking and age, dyspnoea was significantly related to an index of cumulative exposure to oil mist (OR 1.44, P = 0.006/10 The proportion of MAC+ subjects was similar in the two groups. However, after adjustment for baseline FEV1 and age, the dose-response slope was significantly steeper among exposed workers than among controls (P = 0.01), a finding indicating airway hyperresponsiveness in the exposed workers. Furthermore, the dose-response slope was significantly related to baseline FEV1, age, and, after adjustment for FEV1, the index of cumulative exposure to oil (P = 0.004). CONCLUSION: Subjects with exposure to soluble oil mist in the metal industry are at risk of developing both respiratory symptoms and airway hyperresponsiveness.
PMCID: PMC1128592  PMID: 9038798
15.  Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells. 
Journal of Virology  1996;70(10):7190-7197.
Herpes simplex virus type 1 (HSV-1) plasmid vectors have promise for genetic intervention in the brain, but several problems caused by the helper virus have compromised their utility. To develop a helper virus-free packaging system for these vectors, the DNA cleavage/packaging signals were deleted from a set of cosmids that represents the HSV-1 genome. Following cotransfection into cells, this modified cosmid set supported replication and packaging of vector DNA. However, in the absence of the DNA cleavage/packaging signals, the HSV-1 genome was not packaged, and consequently vector stocks were free of detectable helper virus. In the absence of helper virus, the vectors efficiently infected rat neural cells in culture or in the brain with minimal cytopathic effects. beta-galactosidase-positive cells were observed for at least 1 month in vivo, and vector DNA persisted for this period. This system may facilitate studies on neuronal physiology and potential therapeutic applications.
PMCID: PMC190772  PMID: 8794366
16.  Survey of the respiratory health of the workers of a talc producing factory. 
OBJECTIVES--To assess the effect of an occupational exposure to talc dust on respiratory health. METHODS--166 talc millers from a French factory underwent spirometry and filled in a standardised respiratory questionnaire during their annual medical visit in 1989. A full sized chest radiograph taken in 1987 for the subjects hired before 1982 was also available, for the others a radiograph taken when hired was used. Radiography was repeated in 1992 for all subjects still active at this date (n = 139). The occupational exposure to talc dust was characterised for each workplace with 1440 personal samples collected since 1986 and by semiquantitative estimates of the historical exposure. RESULTS--The geometric mean (range) of estimated exposure was 1.87 (0.5 to 50) mg/m3 and the estimated cumulative exposure at the date of spirometry was > 150 y mg/m3 for 41 subjects. After adjustment for smoking in a linear model the standardised residual values of both forced vital capacity and forced expiratory volume in one second decreased significantly with increasing exposure. The prevalence of dyspnoea also increased after adjustment for smoking categories and age in a logistic regression. The prevalence of small radiological opacities was significantly related to age and to the exposure after adjustment for age and smoking categories. The incidence of new opacities between the two radiographs (11 new opacities with a profusion higher than 0/1) was significantly related to smoking (10 out of 11 are smokers) but not to the exposure. CONCLUSION--This study shows an effect of high levels of talc dust both on functional variables and on the prevalence of small radiological images, but provides no clear evidence about the possible effect of present levels of exposure.
PMCID: PMC1128266  PMID: 7670622
17.  A mortality study among mild steel and stainless steel welders. 
A mortality study was carried out in conjunction with the European mortality study among welders coordinated by the International Agency for Research on Cancer (IARC). The study was aimed at assessing risks for lung cancer in relation to exposure to asbestos, welding fumes containing chromium and nickel, and tobacco smoke. The study included a cohort of 2721 welders and an internal comparison group of 6683 manual workers employed in 13 factories in France. The mortality of the two cohorts was studied from 1975 to 1988 by the historical prospective method. Job histories of welders were traced including welding processes used, metals welded, and proportion of worktime spent in welding. Data on smoking habits were collected from medical records. The observed number of deaths were compared with those expected (standardised mortality ratio (SMR)) based on national rates with adjustments for age, sex, and calendar time. The smoking habits of 87% of the whole study population were known. The distribution of welders and controls according to smoking was not statistically different. The overall mortality was slightly higher for welders (SMR = 1.02, 95% confidence interval (95% CI) 0.89-1.18) than for controls (SMR = 0.91, 95% CI 0.84-0.99). For lung cancer, the SMR was 1.24 (95% CI 0.75-1.94) for welders, whereas the corresponding value was lower for controls (SMR = 0.94, 95% CI 0.68-1.26). The SMR for lung cancer was 1.59 among non-shipyard mild steel welders (95% CI 0.73-3.02). This contrasted with the results for all stainless steel welders (SMR = 0.92, 95% CI 0.19-2.69), and for stainless steel welders predominantly exposed to chromium VI (SMR = 1.03, 95% CI 0.12-3.71). Moreover, SMRs for lung cancer for mild steel welders tended to increase with duration of exposure and time since first exposure, leading to significant excesses for duration > or = 20 years and latency > or = 20 years. Such a pattern was not found for stainless steel welders.
PMCID: PMC1061270  PMID: 8457490
18.  Characterization of F107 fimbriae of Escherichia coli 107/86, which causes edema disease in pigs, and nucleotide sequence of the F107 major fimbrial subunit gene, fedA. 
Infection and Immunity  1992;60(5):1963-1971.
F107 fimbriae were isolated and purified from edema disease strain 107/86 of Escherichia coli. Plasmid pIH120 was constructed, which contains the gene cluster that codes for adhesive F107 fimbriae. The major fimbrial subunit gene, fedA, was sequenced. An open reading frame that codes for a protein with 170 amino acids, including a 21-amino-acid signal peptide, was found. The protein without the signal sequence has a calculated molecular mass of 15,099 Da. Construction of a nonsense mutation in the open reading frame of fedA abolished both fimbrial expression and the capacity to adhere to isolated porcine intestinal villi. In a screening of 28 reference edema disease strains and isolates from clinically ill piglets, fedA was detected in 24 cases (85.7%). In 20 (83.3%) of these 24 strains, fedA was found in association with Shiga-like toxin II variant genes, coding for the toxin that is characteristic for edema disease strains of E. coli. The fimbrial subunit gene was not detected in enterotoxigenic E. coli strains. Because of the capacity of E. coli HB101(pIH120) transformants to adhere to isolated porcine intestinal villi, the high prevalence of fedA in edema disease strains, and the high correlation with the Shiga-like toxin II variant toxin-encoding genes, we suggest that F107 fimbriae are an important virulence factor in edema disease strains of E. coli.
PMCID: PMC257102  PMID: 1348723
19.  Mortality study among workers producing ferroalloys and stainless steel in France. 
A mortality study was carried out among the workers of a plant that had produced ferrochromium and stainless steel, and was still producing stainless steel, in order to determine whether exposure to chromium compounds, to nickel compounds, and to polycyclic aromatic hydrocarbons (PAH) could result in a risk of lung cancer for the exposed workers. The cohort comprised 2269 men whose vital status were recorded between 1 January 1952 and 31 December 1982. The smoking habits of 67% of the cohort members were known from medical records. The observed numbers of deaths were compared with the expected ones based on national rates with adjustment for age, sex, and calendar time. A low mortality, achieving statistical significance, was found from all causes (observed = 137, standardised mortality ratio (SMR) = 0.82) and from benign respiratory diseases (observed = one, SMR = 0.15). With regard to mortality from lung cancer, a non-significant excess appeared in the whole cohort (observed = 12, SMR = 1.40). Among the exposed workers, however, a significant lung cancer excess was found (observed = 11, SMR = 2.04) that contrasted with a low SMR (0.32) in the non-exposed group. This excess is unlikely to be explained by smoking, as the tobacco consumption of these two groups was similar. No trend was observed for mortality from lung cancer either according to time since first exposure, or according to duration of exposure. A nested case-control study clearly suggested that this excess of deaths from lung cancer was attributable to former PAH exposures in the ferrochromium production workshops rather than to exposures in the stainless steel manufacturing areas.
PMCID: PMC1035228  PMID: 2393634
20.  Mitochondrial calcium uptake during infection of chicken embryo cells with Semliki Forest virus. 
Journal of Virology  1979;29(1):143-152.
The key role of the mitochondria in the regulation of cellular Ca2+ led to a study of mitochondrial Ca2+ uptake during the infection of chicken embryo cells with Semliki Forest virus. Mitochondrial Ca2+ uptake was stimulated during the first 5 h of infection but declined later in infection. The early stimulation suggests an increase of cytoplasmic ionized Ca2+, whereas the later decrease indicates mitochondrial injury. This functional deterioration was correlated with an increase of the permeability of the inner mitochondrial membrane. Polarographic experiments showed that electron transport is impaired, whereas transduction of energy to Ca2+ uptake is intact.
PMCID: PMC353089  PMID: 430590

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