The Appearance of Endothelium in Small Arteries After Treatment with 5-Fluorouracil. An Electron Microscopic Study of Late Effects in Rabbits

Cardiotoxicity is an unexplained toxic manifestation of 5-fluorouracil (5-FU). Its possible mechanism could be a direct cytotoxic effect on the vascular endothelium. We have tested this hypothesis in an experimental study in rabbits, using scanning and transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear). The perfusion fixation method at physiological pressure and temperature was used. Both local and systemic effects of 5-FU on endothelium were studied 1, 3, 7, 14 and 30 days after in vivo treatment with 5-FU. Fifteen rabbits were used and five additional animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell oedema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter, a scale of negative points (0.0-3.0) was used. We found severe cell damage with accompanying thrombus formation. The findings support the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on endothelium, is the pathophysiological mechanism behind 5-FU cardiotoxicity

The Influence of 5-Fluorouracil on the Endothelium in Small Arteries. An Electron Microscopic Study in Rabbits

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU induced cardiotoxicity is a still relatively unknown side-effect of this drug. This phenomenon could be due to a direct cytotoxic effect on the endothelial cells. We tested this hypothesis in an experimental study in rabbits, by scanning or transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear) after in vivo treatment with 5-FU. Both local and systemic effects of 5-FU on endothelium were studied 15, 30, 60 and 120 minutes after intra-arterial or intraperitoneal treatment. Perfusion fixation at physiological pressure and temperature was used in order to minimize damage to the endothelium during the preparation procedure. Eighteen rabbits weighing 2.5-3.0 kg were used, and 6 animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell edema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter a scale of negative points was used. Irreversible cell damage was observed in 5-FU treated animals: disruption of the endothelial sheet and patchy exposure of the subendothelium, sometimes as a focus for thrombus formation. Our findings support the hypothesis that the thrombogenic effect of 5-FU secondary to its direct cytotoxic effect on endothelium might be one of the pathophysiological mechanisms behind 5-FU induced cardiotoxicity

Identification of a target antigen in human anti-tubular basement membrane nephritis

Identification of a target antigen in human anti-tubular basement membrane nephritis. Sera from two patients with primary anti-tubular–basement–membrane–mediated tubulointerstitial nephritis, one a renal allograft recipient and the other with spontaneous anti-tubular–basement–membrane disease, were analyzed for the specificity of their autoantibodies. Both sera had circulating antibodies that reacted by ELISA with extracts of tubular basement membrane from several species, but failed to react significantly with extracts of glomerular basement membrane. Reactive antigen was solubilized with 6 M guanidine-HCl, 6 M urea, with reduction and alkylation, and with sodium dodecylsulfate. Digestion of the basement membrane with collagenase released relatively small quantities of antigen from the membrane, and trypsin and pepsin destroyed its antigenicity. The antigenic activity was characterized with respect to its size distribution by gel filtration and by immuno-overlay analysis of protein blots. Collectively, the results indicate that the major reactivity of both sera is directed towards a Mr 58,000 component that is unique to the tubular basement membrane. Minor reactivities toward high molecular weight components common to both glomerular and tubular basement membranes were detected by immuno-overlay analysis. This study identifies an antigen that is involved in human anti-tubular–basement–membrane–mediated tubulointerstitial nephritis, and demonstrates an advantage of the use of denaturing extraction over proteolytic methods to prepare the antigen

Common Household Chemicals and the Allergy Risks in Pre-School Age Children

The risk of indoor exposure to volatile organic compounds (VOCs) on allergic airway diseases in children remains unknown.We examined the residential concentrations of VOCs, emitted from building materials, paints, furniture, and other lifestyle practices and the risks of multiple allergic diseases as well as the IgE-sensitization in pre-school age children in Sweden.In a case-control investigation (198 case children with asthma and allergy and 202 healthy controls), air samples were collected in the room where the child slept. The air samples were analyzed for the levels of eight classes of VOCs.A natural-log unit of summed propylene glycol and glycol ethers (PGEs) in bedroom air (equal to interquartile range, or 3.43 - 15.65 µg/m(3)) was associated with 1.5-fold greater likelihood of being a case (95% CI, 1.1 - 2.1), 1.5-fold greater likelihood of asthma (95% CI, 1.0 - 2.3), 2.8-fold greater likelihood of rhinitis (95% CI, 1.6 - 4.7), and 1.6-fold greater likelihood of eczema (95% CI, 1.1 - 2.3), accounting for gender, secondhand smoke, allergies in both parents, wet cleaning with chemical agents, construction period of the building, limonene, cat and dog allergens, butyl benzyl phthalate (BBzP), and di(2-ethylhexyl)phthalate (DEHP). When the analysis was restricted to the cases, the same unit concentration was associated with 1.8-fold greater likelihood of IgE-sensitization (95% CI, 1.1 - 2.8) compared to the non-IgE sensitized cases. No similar associations were found for the other classes of VOCs.We propose a novel hypothesis that PGEs in indoor air exacerbate and/or induce the multiple allergic symptoms, asthma, rhinitis and eczema, as well as IgE sensitization respectively

Can air pollution affect tear film stability? a cross-sectional study in the aftermath of an explosion accident

<p>Abstract</p> <p>Background</p> <p>After an explosion and fire in two tanks containing contaminated oil and sulphur products in a Norwegian industrial harbour in 2007, the surrounding area was polluted. This caused an intense smell, lasting until the waste was removed two years later. The present study reports examinations of tear film break up time among the population. The examinations were carried out because many of the people in the area complained of sore eyes. The purpose of the study was to assess the relationship between living or working close to the polluted area and tear film stability one and a half years after the explosion.</p> <p>Methods</p> <p>All persons working or living in an area less than six kilometres from the explosion site were invited to take part in the study together with a similar number of persons matched for age and gender living more than 20 kilometres away. Three groups were established: workers in the explosion area and inhabitants near the explosion area (but not working there) were considered to have been exposed, and inhabitants far away (who did not work in the explosion area) were considered to be unexposed. A total of 734 people were examined, and the response rate was 76 percent. Tear film stability was studied by assessing non-invasive break-up time (NIBUT) using ocular microscopy. In addition Self-reported Break Up Time (SBUT) was assessed by recording the time the subject could keep his or hers eyes open without blinking when watching a fixed point on a wall. Background information was obtained using a questionnaire. Non-parametric Wilcoxon-Mann-Whitney-tests with exact p-values and multiple logistic regression analyses were performed.</p> <p>Results</p> <p>Both NIBUT and SBUT were shorter among the male exposed workers than among the inhabitants both near and far away from the explosion area. This was also found for SBUT among males in a multiple logistic regression analysis, adjusting for age and smoking.</p> <p>Conclusions</p> <p>Reduced tear film stability was found among workers in an area where an explosion accident had occurred.</p