Recombinant soluble murine IL-4 receptor can inhibit or enhance IgE responses in vivo

This study examines the effects of soluble IL-4R (sIL-4R) administration on IgE production in vivo by using an anti-IgD injection model. Anti-IgD-treated mice were given various doses of sIL-4R or anti-IL-4 mAb over a 3-day period and serum IgE levels were determined by ELISA on day 9. The sIL-4R inhibited IgE production by up to 85%. Anti-IL-4 mAb administration resulted in comparable levels of inhibition at considerably lower doses. The disparity in efficacy between sIL-4R and anti-IL-4 mAb was likely the result of differences in the biodistribution and in vivo half-life of the two IL-4-binding proteins. The specificity of the sIL-4R inhibitory effect was assessed by mixing sIL-4R with various concentrations of IL-4 before injection. Exogenous IL-4 partially overcame the inhibitory effect of high-dose sIL-4R or anti-IL-4 mAb. Unexpectedly, coadministration of suboptimal concentrations of anti-IL-4 mAb or sIL-4R with IL-4 resulted in superinduction of the IgE response. This stimulatory effect was dose dependent for both IL-4 and the IL-4 cognates and was not seen in the absence of exogenous IL-4 over the entire concentration range tested for either sIL-4R or anti-IL mAb. The results indicate that sIL-4R can block IgE secretion by neutralizing endogenous IL-4. Furthermore, sIL-4R can enhance, in a dose-dependent manner, the biologic effects of exogenously administered IL-4, presumably by altering the biodistribution of the cytokine. These findings suggest two alternative applications for cytokine-binding proteins, i.e., 1) as antagonists of biologic activities of endogenously produced cytokines and, 2) as vehicles for cytokine delivery.     

The effects of welding parameters on ultra-violet light emissions, ozone and CrVI formation in MIG welding

Topographical and quantitative features of medial thalamic neurons in which aspartate (ASP) or glutamate (GLU) might act as neurotransmitters were investigated in the rat. The calcium-binding protein calbindin D-28k (CB) was exploited as a marker of neuronal subsets, thus allowing us to study also the relationships between the CB-containing neurons and those immunoreactive to excitatory amino acids. Double immunocytochemistry of ASP and CB or GLU and CB was performed in 40-microm-thick sections. The three markers were distributed in the thalamic midline, mediodorsal, anterior intralaminar and ventromedial nuclei, with regional variations. ASP-immunoreactive neurons appeared more numerous than the GLU-immunoreactive ones throughout these structures; ASP-CB or GLU-CB double-immunostained neurons were evident. ASP-, GLU- and CB-immunoreactive cells were then quantitatively evaluated in 5-microm-thick consecutive sections. Interindividual variations and different anti-ASP and anti-GLU antibodies did not result in significant differences. ASP and GLU were not co-localized. Single ASP- or GLU-immunoreactive neurons accounted for 60% of the total number of immunostained cells, and single ASP-immunopositive cells represented more than half of these neurons. Among the CB-immunoreactive cells (40% of the total), half were double immunostained; the proportion of double CB-ASP-immunopositive neurons was sevenfold higher than that of the CB-GLU-immunoreactive ones. These results indicate that ASP may act as excitatory neurotransmitter in a relatively high proportion of medial thalamic neurons, in which ASP frequently coexists with CB. Approximately 50% of the CB-immunoreactive cells did not contain either ASP or GLU, suggesting that some medial thalamic neurons may utilize a different neurotransmitter.     

Pattern recognition classification of the site of nephrotoxicity based on metabolic data derived from proton nuclear magnetic resonance spectra of urine

The computer-based pattern recognition procedures of nonlinear mapping and principal-component analysis have been applied to analyze 1H NMR-generated metabolic data on the biochemical effects of 15 acute nephrotoxin treatments affecting the renal cortex and/or renal medulla in rats. The 1H NMR signal intensities for 16 urinary metabolites representative of several major intermediary biochemical pathways were estimated using either a simple semiquantitative scoring system or complete peak intensity quantitation. NMR-derived data were treated as input coordinates in a multidimensional metabolic space and were analyzed by pattern recognition methods through which the dimensionality was reduced for display and categorization purposes. Different nephrotoxin treatments were initially classified using semiquantitative metabolite scores on the basis of their 1H NMR-detectable biochemical effects, and a good separation of renal cortical toxin treatments from renal medullary toxin treatments was achieved. The refinement of using exact peak heights rather than metabolic data scores utilized the available metabolic information more fully and provided a unique classification of each type of toxin according to its pattern of biochemical effects and site of toxic action. Principal-component analysis provided consistently better results than did nonlinear mapping in terms of discrimination between different sites of toxicity, and maps generated from correlation matrices gave improved discrimination, compared with those based directly on the original metabolic data. A comparison between the use of an added internal quantitation standard (3-trimethylsilyl-[2,2,3,3-2H4]-1-propionate) and independently determined glucose excretion rates for scaling to the NMR-detected urinary glucose levels demonstrated that the consistent classification of site-specific nephrotoxicity was independent of the quantitation standard used. This study has provided a rigorous assessment of data processing, relative quantitation, and pattern recognition methods, and the utility of applying these methods to the classification of NMR-derived toxicological data. The considerable potential of the NMR-pattern recognition approach in the assessment of nephrotoxicity has also been confirmed with the discovery of new combinations of molecular markers of renal cellular damage.     

Safe management of dermolipomas

Most reports on dermolipomas describe the serious complications arising from their removal. The aim of this article was to describe a safe and effective method of removing dermolipomas. Forty-five consecutive eligible patients underwent surgical removal of their dermolipomas over a 20-year period. Of the two complications, only one, a restrictive symblepharon, required further surgery. The techniques for excising simple dermolipomas and dermolipomas associated with a deformity of the lateral canthal angle are described. Safe removal of dermolipomas may be accomplished with minimal resection of the conjunctiva, including the pilosebaceous area, identification of contiguous structures, and removal of only that portion of the dermolipoma anterior to the lateral orbital rim.     

In vitro inhibition of carnitine acyltransferase activity in mitochondria from rat and mouse liver by a diethylhexylphthalate metabolite

The effects of mono(2-ethyl-5-oxohexyl)phthalate [ME(O)HP], a di(2-ethylhexyl)phthalate (DEHP) metabolite and a potent peroxisomal inducer, on the mitochondrial beta-oxidation were investigated. In isolated rat hepatocytes, ME(O)HP inhibited long chain fatty acid oxidation and had no effect on the ketogenesis of short chain fatty acids, suggesting that the inhibition occurred at the site of carnitine-dependent transport across the mitochondrial inner membrane. In rat liver mitochondria, ME(O)HP inhibited carnitine acyltransferase I (CAT I; EC 2.3.1.21) competitively with the substrates palmitoyl-CoA and octanoyl-CoA. An analogous treatment of mouse mitochondria produced a similar competitive inhibition of palmitoyl-CoA transport whereas ME(O)HP exposure with guinea pig and human liver mitochondria revealed little or no effect. The addition of clofibric acid, nafenopin or methylclofenopate revealed no direct effects upon CAT I activity. Inhibition of transferase activity by ME(O)HP was reversed in mitochondria which had been solubilized with octyl glucoside to expose the latent form of carnitine acyltransferase (CAT II), suggesting that the inhibition was specific for CAT I. Our results demonstrate that in vitro ME(O)HP inhibits fatty acid oxidation in rat liver at the site of transport across the mitochondrial inner membrane with a marked species difference and support the idea that induction of peroxisome proliferation could be due to an initial biochemical lesion of the fatty acid metabolism.