Occupational skin diseases: actual state analysis of patient management pathways in 28 European countries.

BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment and rehabilitation in different European countries. METHODS: A questionnaire-based survey of the current situation regarding OSD patient management pathways was carried out with experts on occupational dermatology and/or occupational medicine from 28 European countries contributing to the European Cooperation in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks (synonyms: insurance against work accidents and occupational injuries; statutory social accident insurance)]. Legal standards for the assessment of occupationally triggered diseases with a genetic background differ between different countries, however, in most European member states recognition as OSD is possible. In one-third of the countries UV light-induced tumours can be recognized as OSD under specific conditions. CONCLUSION: OSD definitions vary between European countries and are not directly comparable, which hampers comparisons between statistics collected in different countries. Awareness of this fact and further efforts for standardization are necessary.

Enhanced susceptibility of obese mice to glycidamide-induced sperm chromatin damage without increased oxidative stress.

Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.

Inflammation in induced sputum after aluminium oxide exposure: an experimental chamber study.

INTRODUCTION: Workers in aluminium production are exposed to a complex mixture of particles and gases potentially harmful to the airways, among them aluminium oxide (Al2O3). With the use of an exposure chamber, we aimed to examine the effects of short-term controlled exposure to Al2O3 on lung function and inflammatory markers in healthy volunteers. METHODS: 15 men (age 19-31) were exposed in random order to clean air or Al2O3 particles (3.8-4.0 mg/m(3)) for 2 h including 30 min exercise (stationary bike, 75 W). The permissible exposure level (PEL) for Al2O3 by Occupational Safety and Health Administration, USA, is 5 mg/m(3) time weighted average (TWA). Sham and particle exposures were separated by at least 2 weeks. Spirometry was carried out, and induced sputum and blood samples were collected 48 h before and 4 and 24 h after exposure. RESULTS: Levels of sputum neutrophils (mean (±SEM)) was increased 24 h post-Al2O3 vs pre-Al2O3 exposure (43% (4) vs 31% (4), p=0.01) and the protein level of interleukin (IL)-8 had a 4.8 (0.9)-fold change increase 24 h after exposure (p<0.01). Following Al2O3 exposure, gene signatures in sputum were significantly increased related to several pathways. CONCLUSIONS: The present study suggests that controlled exposure to Al2O3 particles at levels below PEL (TWA) induces airway inflammation in healthy humans marked by elevated neutrophils and elevated IL-8. In addition, increased expression of genes associated with several biological processes was observed in sputum. Interestingly, inhaled Al2O3-induced effects were localised to the airways and not systemic.

Routine disc diffusion antimicrobial susceptibility testing of Clostridium difficile and association with PCR ribotype 027.

Reduced susceptibility to metronidazole and vancomycin in Clostridium difficile has been reported, which emphasises the need for simple antimicrobial susceptibility testing methods. The aim of this study was to apply a published disc diffusion method and zone diameter breakpoint correlates to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) epidemiological minimum inhibitory concentration (MIC) cut-off values in a routine setting. Metronidazole and vancomycin zone diameters from 2702 isolates were recorded. Fifteen isolates had a metronidazole zone diameter below the published breakpoint (<23 mm) and five isolates had a vancomycin zone diameter below the published breakpoint (<19 mm), most of which were polymerase chain reaction (PCR) ribotype 027. The total number of PCR ribotype 027 was 29 (1.1 %). Overall, C. difficile PCR ribotype 027 isolates had smaller zone diameters than non-027 isolates. The disc diffusion method is very simple and inexpensive, and the published zone diameter breakpoints will detect C. difficile isolates with reduced susceptibility to metronidazole and vancomycin.

Antimicrobial susceptibility testing of Clostridium difficile using EUCAST epidemiological cut-off values and disk diffusion correlates.

With the emergence of reduced susceptibility of Clostridium difficile to metronidazole and vancomycin the value of antimicrobial susceptibility testing has increased. The aim of our study was to evaluate disk diffusion for susceptibility testing of C. difficile by comparing disk diffusion results with MICs from gradient tests and to propose zone diameter breakpoint correlates for the EUCAST epidemiological cut-off values (ECOFFs) recently published. We tested 211 clinical isolates of C. difficile, from patients with diarrhoea hospitalized at Aarhus and Odense University Hospitals, Denmark. Furthermore, ten clinical isolates of C. difficile from the Anaerobe Reference Laboratory, University Hospital of Wales, with known reduced susceptibility to either metronidazole or vancomycin, were included. Isolates were tested with Etest gradient strips and disk diffusion towards metronidazole, vancomycin and moxifloxacin on Brucella Blood Agar supplemented with hemin and vitamin K. We found an excellent agreement between inhibition zone diameter and MICs. For each MIC value, the inhibition zones varied from 0 to 8 mm, with 93% of values within 6 mm for metronidazole, 95% of values within 4 mm for vancomycin, and 98% of values within 4 mm for moxifloxacin. With proposed zone diameter breakpoints for metronidazole, vancomycin and moxifloxacin of WT ≥ 23 mm, WT ≥ 19 and WT ≥ 20 mm, respectively, we found no very major errors and only major errors below 2%. In conclusion, we suggest that disk diffusion is an option for antimicrobial susceptibility testing of C. difficile.

The constitutive level of vascular endothelial growth factor (VEGF) is more important than hypoxia-induced VEGF up-regulation in the angiogenesis of human melanoma xenografts.

Angiogenesis of tumours might develop as a result of environmental conditions, such as hypoxia, and/or as a result of genetic alterations specific for tumour cells. The relative contributions of these mechanisms were investigated by comparing the in vivo expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) to the hypoxic fraction, the angiogenic potential and the vascular density of four human melanoma lines (A-07, D-12, R-18, U-25) grown intradermally in Balb/c nu/nu mice. VEGF expression, bFGF expression and expression of pimonidazole, a marker of hypoxic cells, were investigated by immunohistochemistry. An association between high VEGF and bFGF expression and high angiogenic potential was detected, suggesting an important role for VEGF/bFGF in the angiogenesis of melanomas. High VEGF/bFGF expression was also related to low hypoxic fraction and high vascular density. Thus, the constitutive, genetically determined level of VEGF was probably more important than hypoxia-induced upregulation in the angiogenesis of the melanoma xenografts.

Serum eosinophil cationic protein in asthma of farmers.

OBJECTIVE: There is need for relevant markers of bronchial inflammation in epidemiologic studies of asthma. Serum eosinophil cationic protein (ECP) is a marker of eosinophil inflammation and asthma activity. We have studied serum ECP in atopic farmers with current asthma, in non-atopic asthmatics and in non-asthmatic, non-atopic controls. METHODS AND RESULTS: In a cross-sectional study of a representative sample of 8,482 farmers in Norway, asthma was recorded using a self-administered questionnaire; spirometry and serum sampling were performed on all of them. Atopy was screened with Phadiatop and RAST analyses to the mites Lepidoglyphus destructor and Tyrophagus putrescentiae in all asthma cases and controls. All the identified atopics had additional RAST analyses on a set of allergens. Serum ECP was tested in 60 persons with current asthma and atopy (mean 16.2, 95% CI 13.2-19.3), 127 non-atopic asthmatics (mean 9.1, 95% CI 8.0-10.2) and 39 non-atopic controls (mean 5.5, 95% CI 4.0 7.0). ECP levels in atopic asthmatics were associated with number of positive allergens and reduction of FEVI values. Moreover, the ECP levels were elevated with allergy to swine, cow, D. pteronyssinus, L. destructor, A. siro, T. putrescentiae, timothy grass and the cereal grains: wheat, oat, barley and rye. CONCLUSION: Serum ECP seems feasible as an indicator of inflammatory activity in epidemiological studies of current allergic asthma, and may help to indicate the importance of specific allergens. Although the ECP values were significantly more elevated in atopic than in non-atopic asthma, elevated serum ECP was not specific for atopic asthma.

Incidence of cancer among welders and other shipyard workers with information on previous work history.

The incidence of cancer among 4480 shipyard workers, including 861 welders, was investigated for a potential relationship between exposure to welding fumes and lung cancer. A subcohort of 3150 workers with information on previous work history was studied separately. This investigation is a historical prospective cohort study. Environmental air samples were collected in 1973, 1977, and 1989. Information on smoking habits was surveyed in 1976 and 1984. The employment work histories were collected from the personnel register. There were 411 observed cancers of all sites versus 387.5 expected, and 45 cases of lung cancer versus 51.3 expected. Nine cases of lung cancer were found among the welders versus 7.1 expected. Among 310 former seamen with welding experience, there was 1 case of lung cancer versus 2.1 expected. These shipyard workers showed no excess risk of lung cancer. Tobacco smoking and asbestos exposure are potential confounders in the study. There was no clear relationship between exposure to welding fumes and lung cancer, but welders with the longest experience had a relative risk of 1.9 for lung cancer. The differences in lung cancer incidence among the different shipyard workers could not be attributed to differences in recruitment patterns or previous work history.

No association between radiosensitivity and TP53 status, G1 arrest or protein levels of p53, myc, ras or raf in human melanoma lines.

PURPOSE: First, to investigate whether TP53 status and/or radiation-induced G1 arrest are associated with radiosensitivity, and, second, to detect possible associations between protein levels of p53, myc, ras or raf and radiosensitivity and to investigate whether hypoxia-induced changes in the levels of these proteins are related to hypoxia-induced changes in radiosensitivity in human melanoma lines. MATERIALS AND METHODS: Radiosensitivity was assessed by clonogenic assays. TP53 status was investigated at the genomic level by constant denaturant gel electrophoresis and at the cDNA level by sequencing. G1 arrest was investigated by flow cytometric analysis of DNA. Protein expression of hypoxia-treated and untreated cells was assessed by flow cytometric measurements and Western blotting. RESULTS: Considerable differences in radiosensitivity were detected among melanoma lines with wild-type TP53. Only a fraction of the melanoma cells, differing between the lines, was arrested in G1. No association between the fraction of arrested cells and radiosensitivity was detected. Protein levels of p53, myc, ras or raf were not associated with radiosensitivity. Hypoxia-induced changes in p53, ras and raf levels were detected in all cell lines. Changes in the level of myc protein were detected for two of the four cell lines, while hypoxia-induced changes in radiosensitivity were observed only for one. CONCLUSIONS: Differences in radiosensitivity among melanoma lines cannot be elucidated by TP53 status, differences in G1 arrest or different levels of p53, myc, ras or raf proteins. Hypoxia-induced changes in p53, myc, ras or raf levels do not seem to be related to hypoxia-induced changes in radiosensitivity.

Hypoxia-induced metastasis of human melanoma cells: involvement of vascular endothelial growth factor-mediated angiogenesis.

Tumour cells exposed to hypoxia have been shown to up-regulate the expression of vascular endothelial growth factor (VEGF). The purpose of the present work was to investigate whether hypoxia-induced VEGF up-regulation can result in increased metastatic efficiency of human melanoma cells. Two melanoma lines, one showing high (A-07) and the other showing low (D-12) VEGF secretion under aerobic conditions, were included in the study. Cell cultures were exposed to hypoxia (oxygen concentrations < 10 ppm) in vitro and metastatic efficiency, i.e. lung colonization efficiency, as well as transplantability and angiogenic potential were assessed in BALB/c-nu/nu mice Both cell lines showed significantly increased VEGF secretion under hypoxic conditions as measured by enzyme-linked immunosorbent assay The D-12 cells showed increased metastatic efficiency, transplantability and angiogenic potential following exposure to hypoxia. The metastatic efficiency increased with the duration of the hypoxia treatment and decreased with the time after reoxygenation. The A-07 cells on the other hand showed unchanged metastatic efficiency, transplantability and angiogenic potential following exposure to hypoxia. Both cell lines showed significantly decreased metastatic efficiency and angiogenic potential in mice treated with neutralizing antibody against VEGF. These results suggest that (a) VEGF is a limiting factor for the rate of angiogenesis in low but not in high VEGF-expressing melanomas under normoxic conditions and (b) transient hypoxia might promote the development of metastases in low VEGF-expressing melanomas by upregulating the expression of VEGF and hence enhancing the angiogenic potential of the tumour cells.

Hypoxia induces p53 accumulation in the S-phase and accumulation of hypophosphorylated retinoblastoma protein in all cell cycle phases of human melanoma cells.

Hypoxia has been shown to induce accumulation of p53 and of hypophosphorylated retinoblastoma protein (pRb) in tumour cells. In this study, the cell cycle dependence of p53 accumulation and pRb hypophosphorylation in four human melanoma cell lines that are wild type for p53 was investigated using two-parameter flow cytometry measurements of p53 or pRb protein content and DNA content. The hypoxia-induced increase in p53 protein was higher in S-phase than in G1 and G2 phases in all cell lines. The accumulation of p53 in S-phase during hypoxia was not related to hypoxia-induced apoptosis or substantial cell cycle specific cell inactivation during the first 24 h of reoxygenation. pRb was hypophosphorylated in all cell cycle phases by hypoxia treatment. The results did not support a direct link between p53 and pRb during hypoxia because p53 was induced in a cell cycle-specific manner, whereas no cell cycle-dependent differences in pRb hypophosphorylation were detected. Only a fraction of the cell populations (0.60+/-0.10) showed hypophosphorylated pRb. Thus, pRb is probably not the only mediator of the hypoxia-induced cell cycle block seen in all cells and all cell cycle phases. Moreover, the cell cycle-dependent induction of p53 by hypoxia suggests that the primary function of p53 accumulation during hypoxia is other than to arrest the cells.

VEGF, bFGF and EGF in the angiogenesis of human melanoma xenografts.

Vascular endothelial growth factor (VEGF) is a major inducer of angiogenesis in tumors. Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) have both been shown to interact with VEGF. The involvement of VEGF, bFGF, and EGF in melanoma angiogenesis was investigated here. Four human melanoma cell lines (A-07, D-12, R-18, U-25) were included in the study. Angiogenesis was quantified by scoring of tumor-oriented capillaries following intradermal cell inoculation in BALB/c nu/nu mice. VEGF, bFGF and EGF expression and secretion were investigated by Western blotting and enzyme-linked immunosorbent assay, respectively. Immunohistochemistry of xenografts grown intradermally was used to reveal VEGF and bFGF localization in vivo. The rate of angiogenesis differed substantially among the melanoma lines; the sequence from a high to low rate of angiogenesis was: A-07, D-12, R-18, U-25. A-07, which induced the highest rate of angiogenesis, showed a higher rate of VEGF secretion, stronger VEGF staining by immunohistochemistry and higher bFGF expression than the other lines. U-25, which induced the lowest rate of angiogenesis, showed a higher rate of VEGF secretion than D-12 and R-18. A-07 was the only line that showed detectable bFGF secretion, and R-18 was the only line that showed detectable EGF secretion. VEGF is probably important in the angiogenesis of melanomas. However, heterogeneity in rate of angiogenesis among melanomas cannot be attributed to heterogeneity in rate of secretion of VEGF, bFGF and/or EGF only.

Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma.

Tumour cells exposed to hypoxia in vitro can show increased expression of several selected genes, including the gene encoding the vascular endothelial growth factor (VEGF), suggesting that hypoxia followed by reoxygenation might promote the malignant progression of tumours. An in vitro/in vivo study was conducted to investigate whether hypoxia can increase the angiogenic potential of tumour cells through increased VEGF secretion. Four human melanoma cell lines (A-07, D-12, R-18, U-25) were included in the study. Cell cultures were exposed to hypoxia (oxygen concentration <10 p.p.m.) in vitro using the steel chamber method. Rate of VEGF secretion was measured in vitro in aerobic and hypoxic cell cultures by ELISA. Angiogenesis was assessed in vivo using the intradermal angiogenesis assay. Aliquots of cells harvested from aerobic cultures or cultures exposed to hypoxia for 24 h were inoculated intradermally in the flanks of adult female BALB/c-nu/nu mice. Tumours developed and angiogenesis was quantified by scoring the number of capillaries in the dermis oriented towards the tumours. The number of tumour-oriented capillaries did not differ significantly between tumours from hypoxic and aerobic cultures for A-07 and U-25, whereas tumours from hypoxic cultures showed a larger number of tumour-oriented capillaries than tumours from aerobic cultures for D-12 and R-18. The VEGF secretion under aerobic conditions and the absolute increase in VEGF secretion induced by hypoxia were lower for D-12 and R-18 than for A-07 and U-25, whereas the relative increase in VEGF secretion induced by hypoxia was higher for D-12 and R-18 than for A-07 and U-25. VEGF is not a limiting factor in the angiogenesis of some tumours under normoxic conditions. Hypoxia can increase the angiogenic potential of tumour cells by increasing the secretion of VEGF, but only of tumour cells showing low VEGF secretion under normoxia. Transient hypoxia might promote the malignant progression of tumours by temporarily increasing the angiogenic potential of tumour cells showing low VEGF expression under normoxic conditions.

Incidence of lung cancer among shipyard welders investigated for siderosis.

The incidence of lung cancer among 428 shipyard welders exposed for more than ten years to welding fumes was investigated. The welders were examined for siderosis by the Directorate of Labor Inspection in 1975. The present study was a follow-up based on historical information from the Norwegian registry of dust-exposed workers. Twenty-three welders with siderosis, and 156 welders working at the same shipyards as the siderosis cases were studied as sub-cohorts. There was no loss on follow-up. The observation period was 1976 through 1992. There were 32 cases of cancer from all causes vs 41.3 expected. A nonsignificant excess of lung cancer was observed; 10 cases vs 6.5 expected. The incidence of lung cancer was highest for the welders with more than 30 years since first exposure (7 cases vs 4.1 expected). The sub-cohort of welders with siderosis had no case of lung cancer vs 0.5 expected. These welders were assumed to have experienced high exposure levels for welding fumes. The morbidity of cancer from all causes was low for this small group of blue-collar workers, but the incidence of lung cancer was slightly increased. The increase was not attributable to welders with siderosis. Smoking and asbestos exposure are potential confounders.

Hypoxia-induced changes in radiation sensitivity in human melanoma cells: importance of oxygen-regulated proteins, adenylate energy charge and cell cycle distribution.

BACKGROUND AND PURPOSE: The effects of transient hypoxia on the radiation sensitivity of human tumour cells have so far been investigated only to a limited extent, and only up to 12 h after reoxygenation. We irradiated cells shortly after reoxygenation (<1 h) or at prolonged times after reoxygenation (24 h and 48 h) in order to examine possible relationships between changes in radiation sensitivity on the one hand and changes in rates of synthesis of oxygen-regulated proteins, changes in energy metabolism and changes in cell cycle distribution on the other. MATERIALS AND METHODS: Four human melanoma cell lines (A-07, D-12, R-18 and U-25) were included in the study. After hypoxia treatment (4 h or 16 h) and reoxygenation, cells were either irradiated as monolayers at a dose rate of 2.0 cGy/min or prepared for protein analysis, energy charge measurements or flow cytometric measurements of DNA. RESULTS: U-25 was the only line that showed increased radiation sensitivity shortly after reoxygenation, possibly because of extensive energy depletion. A-07 was the only line that showed increased radiation sensitivity at prolonged times after reoxygenation, possibly because of hypoxia-induced changes in the cell cycle distribution. The rates of synthesis of oxygen-regulated proteins (GRP78, GRP94, HSP70 and HSP90) were transiently perturbed to a similar extent in all lines after hypoxia treatment. CONCLUSION: The radiation sensitivity of the human melanoma cell lines was changed only to a minor extent by transient exposure to hypoxia.

Incidence of cancer among Norwegian boiler welders.

OBJECTIVES: The cancer incidence among 2957 boiler welders was investigated. The subjects were registered electrical welders from 1942 to 1981. A subcohort of 606 stainless steel welders was studied separately. METHODS: The investigation was a historical prospective cohort study based on a national registry. The loss of follow up was 4.9%. RESULTS: There were 625 deaths (659 expected). There were 269 cancer cases (264 expected). An excess of lung cancer was found; 50 cases v 37.5 expected. There were three cases of pleural mesotheliomas v 1.1 expected. The subcohort of stainless steel welders had six cases of lung cancer v 5.8 expected, and one case of pleural mesothelioma v 0.2 expected. CONCLUSIONS: The welders in the study were assumed to represent a qualified work force. These welders had a small excess risk of lung cancer. The excess risk did not seem to be associated with stainless steel welding. Smoking and asbestos exposure were potential confounders.

Incidence of cancer among welders of mild steel and other shipyard workers.

The incidence of cancer among 4571 shipyard workers with first employment between 1940 and 1979, including 623 welders of mild steel, was investigated in a historical cohort study. The loss to follow up was 1.1%. The total number of deaths was 1078 (974.5 expected) and there were 408 cases of cancer v 361.3 expected. Sixty five cases of lung cancer were found v 46.3 expected based on the national rates for males. Four pleural mesotheliomas had occurred (1.2 expected), none among the welders. An excess of lung cancers was found among the welders (nine cases v 3.6 expected). There were six cases of lung cancer v 1.6 expected in a high exposure group of 255 welders. A survey of the smoking habits as of 1984 indicated 10%-20% more daily smokers among the shipyard production workers than among Norwegian males. Exposure to smoking and asbestos were confounding variables in this study.

[Medical expert systems. Developmental activities in the Scandinavian countries]. / Medisinske ekspertsystemer. Utviklingsaktiviteter i de nordiske land.

Medical expert systems is a term for computer programs which represent and structure medical knowledge, and which can supplement or replace man in decisionmaking. Several research groups in Denmark, Finland, Norway and Sweden are developing such systems. Many of the projects emphasize educational aspects and also serve to qualify the participants in the project. The medical expert systems are applied to clinical chemistry, neurophysiological testing or intensive care. Within this field of medical expert systems there is much duplication of activities and too little practical application. Usually the systems are developed to be used as functional prototypes and are often not good enough or not intended to be used in daily hospital routines. There should be good prospects in this field in the near future.