Confusion of concepts in mixture toxicology

Regulatory limit values are generally set for single compounds. However, humans are exposed both simultaneously and sequentially to a wide variety of compounds. Some concepts on mixture toxicology are discussed in this introduction to the European Conference on Combination Toxicology. Studies on mixtures are often accompanied by statements about the type of combined action, which can be, for example, additive, synergistic or antagonistic. Unfortunately, comparison of results is hardly possible for various reasons. First, the terminology for indicating combined action is far from consistent. Bearing this in mind, researchers should be explicit in the definitions of terms. Secondly, depending on the model, different conclusions may be drawn from the same results. It is therefore important to provide clear definitions of the null hypothesis. Thirdly, adequate statistical methods should be used for testing the null hypothesis. In the past, many mixtures studies either used no statistics or used statistics incorrectly. Last, but not least, the study should be designed in such a way that it should be possible to obtain clear answers. In this introduction, it is stressed that environmental toxicologists should focus on the low-dose region of the dose-effect curves. It appears that interactions are less plausible at low doses. Dose additivity, however, cannot be excluded.     

Chronic pancreatitis and neoplasia: correlation or coincidence

Renal biopsy specimens from patients with membranous nephropathy (MN) were studied using immunohistochemical labelling to clarify the aetiological significance of Helicobacter pylori antigen in this disease. Sixteen specimens were examined, from 7 male and 9 female MN patients. Renal specimens from patients with diabetic nephropathy and IgA nephropathy, and from autopsied patients without renal diseases were obtained as controls. Immunohistochemical labelling was performed using one polyclonal antibody and three monoclonal antibodies against H. pylori. Specimens from 11 of the MN patients revealed granular deposits along the glomerular capillary walls, which reacted positively with polyclonal antibody after trypsin pretreatment. None of the control specimens revealed positive labelling. The MN specimens showed no positive reaction with the primary antibody, which had been treated for immunoabsorption testing using sonicated H. pylori. We also determined H. pylori status in these MN patients histologically and/or serologically. Of the 11 patients whose glomeruli were positive for anti-H. pylori antibody, 7 were suitable for analysis, and all were regarded as positive for H. pylori infection. These results suggest that the presence of a specific antigen in the glomeruli of patients with MN and H. pylori infection may be involved in the pathogenesis of MN.     

Adenoviral-mediated gene transfer in lymphocytes

Although adenovirus can infect a wide range of cell types, lymphocytes are not generally susceptible to adenovirus infection, in part because of the absence of the expression of the cellular receptor for the adenoviral fiber protein. The cellular receptor for adenovirus and coxsackievirus (CAR) recently was cloned and shown to mediate adenoviral entry by interaction with the viral fiber protein. We show that the ectopic expression of CAR in various lymphocyte cell lines, which are almost completely resistant to adenovirus infection, is sufficient to facilitate the efficient transduction of these cells by recombinant adenoviruses. Furthermore, this property of CAR does not require its cytoplasmic domain, consistent with the idea that CAR primarily serves as a high affinity binding site for the adenoviral fiber protein, and that viral entry is mediated by interaction of the viral penton base proteins with cellular integrins. As a demonstration of their functional utility, we used CAR-expressing lymphocytes transduced with an adenovirus expressing Fas ligand to efficiently kill Fas receptor-expressing tumor cells. The ability to efficiently manipulate gene expression in lymphocyte cells by using adenovirus vectors should facilitate the functional characterization of pathways affecting lymphocyte physiology.     

Testing to predict outcome after transurethral resection of the prostate

PURPOSE: We assessed the ability of routine clinical tests to predict outcome following transurethral resection of the prostate. MATERIALS AND METHODS: A total of 556 men randomized into a trial of surgery versus watchful waiting was evaluated preoperatively with symptom interview, quality of life assessment, uroflowmetry, urinalysis, standard chemistry panel, post-void residual urine determination and cystoscopy. The ability to predict avoidance of postoperative complications, and improvement in quality of life and genitourinary symptoms was assessed in the 249 men randomized to undergo transurethral resection of the prostate. RESULTS: Patients with the highest symptom scores were most likely to have symptom improvement and those most bothered by the symptoms were most likely to have improvement in quality of life. No objective tests measuring physiological parameters made clinically significant contributions toward predicting these outcomes. Lower obstructive symptom scores and larger perioperative infusions of intravenous fluids were associated with a greater chance of complications. CONCLUSIONS: Symptom analysis and quality of life assessment are most useful in selecting patients for transurethral resection of the prostate. Objective diagnostic tests are of limited additional benefit.     

Evaluating support services to seniors. A discussion of collaborative research

The difficulties involved in attempting to turn collaboration into partnership are revealed in this article about the relationship between research funders and researchers, specifically government funders and university researchers. Some discussion revolves around the relationships between researchers and among the researchers, practitioners, and consumers. This article also discusses collaborative research relationships by using the evaluation of a support program to seniors as an illustration. Also addressed are how the research revealed the success of the program and the frustrations encountered when government would not act on the findings.     

A microplate fluorimetric assay for transfection of the beta-galactosidase reporter gene

Despite having been first marketed in the 1950s, new designs of progressive addition spectacle lens continue to appear. Some of the recent patent literature is reviewed on the design of such lenses. As well as a number of improvements to general purpose designs, specifically to include aspheric surfaces for the distance portion of progressive lenses, the literature includes a recent patent on an improved version of the Alvarez lateral translation lens system. The optimisation of single vision lens forms in order to extend the depth of field for early presbyopes is also discussed.     

Fatty acids and cancer

When ATP is applied at high concentrations (above 1 mM) to PC12 cells, it produces a rapidly desensitizing peak current followed by a rebound of the current after termination of the ATP application. We expressed P2X2 receptors, which are thought to mediate the ATP currents of PC12 cells, in HEK293 cells and studied the effects of acidification on this 'fading and rebound' phenomenon. We found that the desensitization disappeared after adjusting the low pH (<5.0) of the millimolar ATP concentrations to a more physiological value (pH 7.3). Furthermore, the fading and rebound could also be induced at much lower ATP concentrations by decreasing the pH of the ATP containing application solutions. Thus, it appears this phenomenon is not caused directly by high concentrations of ATP, but is due to a concomitant acidification that occurs when high concentrations of ATP are dissolved in only moderately buffered application solutions.