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1. A significant cytotoxic effect of trypsinized, sensitized cell cultures was observed when re-exposed to Brucella antigens in vitro. 2. The cytometric assay of the toxic effects of Brucella antigens using trypsinized cells from sensitized animals provides an objective measure of induced cellular hypersensitivity.
The cytocidal effect of specifically sensitized lymphoid cells on homologous target cells in culture can be inhibited by small quantities of an imidazole derivative of 6-mercaptopurine (imuran). This inhibition takes place only in the continuous presence of this drug, and at concentrations which apparently do not affect the viability of the attacking lymphoid cells. These results seem to support the contention that RNA-dependent protein synthesis on the part of the lymphoid cells is necessary for a destructive interaction between sensitized node cells and homologous target cells in vitro.
Heat-killed strains of Staphylococcus aureus and Staphylococcus albus can induce in guinea pigs a state of altered reactivity to skin homografts which is indistinguishable from that which results from sensitization with homologous tissues or Group A streptococci. Challenge of suitably prepared recipients with first-set skin homografts obtained from unrelated randomly selected donors elicits white graft reactions or accelerated rejection of such grafts. Other bacteria tested included Lancefield streptococcal groups B, C, D, E, G, H, L, and O, pneumococcus Types II, III, XIV and a rough strain, Corynebacterium xerosis, Bacillus subtilis, Escherichia coli, Aerobacter aerogenes, Salmonella typhimurium, Proteus vulgaris, Neisseria catarrhalis, Haemophilus influenzae, and two human virulent strains of Mycobacterium tuberculosis. None of these microorganisms was active in the induction of homograft sensitivity in the guinea pig. Pretreatment of recipients with Gram-negative bacterial suspensions was associated with a slight increase in the mean survival time of first-set skin homografts. Results of this study suggest the presence in staphylococci, as well as in Group A streptococci, of antigens related in their biologic effects to tissue transplantation antigens.
As measured by [(3)H]thymidine uptake, spleen cells of mice injected 7 d previously with a single dose of cyclophosphamide (Cy) (125 mg x kg (-1)) gave an enhanced response to dextran sulfate (DS), a diminished response to lipopolysaccharide (LPS), and a normal response to concanavalin A. Addition of syngeneic thymocytes to spleen cells inhibited the enhanced response of the cells to DS and slightly enhanced their response to LPS. Pretreatment of thymocytes by 4-hydroxyperoxycyclophosphamide (4HP-Cy) in vitro (an in vitro active derivative of Cy) abrogated the effect of thymocytes on the DS response but not on the LPS response. Pretreatment of spleen cells by small doses of 4HP-Cy (0.1-1.0 mug. ml(-1)) in vitro enhanced the capacity of the cells to respond to DS but either did not affect, or even diminished their capacity to respond to LPS. The enhancement of the DS response by 4HP-Cy treatment could not be detected using spleen cells depleted of T cells or lacking functioning T cells. 4HP-Cy doses more than 3 mug ml(-1) diminished or abolished the capacity of the spleen cells to respond to LPS as well as their capacity to respond to DS. The results show (a) that in contrast to the LPS-reactive B-lymphocyte subset, the proliferative capacity of DS-reactive subset is negatively controlled by a Cy- and 4HP-Cy-sensitive T-cell subset and (b) that these T- suppressor cells are more sensitive to Cy and 4HP-Cy (to their respective active alkylating metabolites) than B lymphocytes and T cells carrying other immunological functions.
Oromucosal (o.m.) administration of interferon-alpha (IFN-alpha) during either allergic sensitization (days 0-6) or the hypersensitive response (days 11 and 12) or both periods caused a dose-dependent reduction in allergen-specific IgE production and allergen-induced eosinophil recruitment in mice sensitized to ragweed pollen, a common allergen in humans. Treatment during the hypersensitive response period alone appeared to be most effective. Oromucosal treatment was as effective as intraperitoneal (i.p.) treatment, with maximum inhibition of both allergen-specific IgE production and allergen-induced eosinophil recruitment observed at a dose of a 1000 IU IFN-alpha. Treatment of animals with up to 10(5) IU murine IFN-alpha/beta (MuIFN-alpha/beta) by either the om. or i.p. route did not inhibit significantly allergen-specific IgG production, which may even have been increased at certain doses of IFN. Treatment of animals with up to 10(5) IU MuIFN-alpha/beta by either the o.m. or i.p. route did not affect significantly total serum IgE or IgG levels. Oromucosal administration of IFN-alpha reduced allergen-specific IgE production and allergen-induced eosinophil recruitment in the absence of detectable toxicity, the induction of H(2) antigen expression, and 2',5'-oligoadenylate synthetase activity associated with parenteral administration of IFN-alpha and thus may find application for the treatment of asthma and associated viral infections.
This study determined the influence of baroreflex sensitivity (BRS) on the rate of urinary sodium excretion and plasma renin activity (PRA) in response to a saline infusion in conscious male rabbits specifically bred for high (Group I; n = 7) and low (Group II; n = 10) BRS and in seven control animals. Only Group II showed significant increases in blood pressure on a chronic high-salt intake. After ensuring that each animal was in sodium balance, a (0.7-0.9%) saline infusion of 3-4 ml/kg per h for 90 min (25% daily sodium intake for each rabbit) was given and urine collected at 15-min intervals via a bladder catheter. No differences were found in control urine volumes, urinary sodium or PRA. Group I excreted over 50% of the sodium load and Group II less than 20% within 90 min. PRA fell by more than 30% within 30 min in six Group I rabbits but decreased by less than 30% or increased in Group II. In the control animals, sodium excretion rates and PRA suppression were also much greater in those with high BRS. A highly significant correlation (r = 0.808, P less than 0.01) was found between the per cent of the sodium load excreted and BRS. It is suggested that the delayed sodium excretion and blood pressure elevation in salt-sensitive subjects may be due to a genetic impairment in baroreflex control of renal sympathetic nerve activity.
Using synthetic peptides representing specific regions of the bovine myelin protein P2, the minimum peptide length requirement for the T-cell epitope necessary for successful production of experimental allergic neuritis (EAN) has been shown to involve residues 61-70 of the P2 protein. In this study, morphometric analysis was used to compare the histologic changes in sciatic nerves of Lewis rats after disease was induced by P2 specific neuritogenic T-cell lines (P(2)3) or, alternatively, by direct inoculation of synthetic peptides representing residues 60-70 or 61-70 of the P2 protein sequence. Inoculation with cell line P(2)3 stimulated with residue 61-70 failed to elicit demyelination in sciatic nerves. However, cells stimulated with residue 60-70 produced inflammation, endoneurial edema, mild demyelination and axonal degeneration within seven days. In contrast, disease induced with either peptide by direct sensitization was more severe. Morphometric analysis revealed that inflammation was most severe in animals sensitized to the decapeptide. In the sciatic nerve, axonal degeneration was proportional in frequency to the extent of inflammation. Inflammation was especially intense in spinal roots with extensive destruction of axons including unmyelinated fibers. Spinal root changes were associated with Wallerian degeneration in the posterior white matter tracts of the spinal cord and were apparently secondary to endoneurial inflammation. Disruption of the blood-nerve-barrier (BNB), evident as physical separation of endothelial cells in association with severe perivascular inflammation, was observed.
We determined whether U-89232, a derivative of the ATP-sensitive potassium (KATP) channel opener cromakalim, is cardioselective and whether its action on the myocardium is still sensitive to glibenclamide. Experiments were performed in open-chest pigs subjected to a 60-min occlusion of the left anterior descending coronary artery (LADCA) and to 2 h of reperfusion. Four groups of animals were studied (n = 6 each). Animals received either U-89232, 3 mg/kg i.v. over a 15-min period (U), or glibenclamide, a selective KATP channel blocker, 1 mg/kg i.v. over a 15-min period (GLI) before the LADCA occlusion. In the GLI + U group, first glibenclamide (1 mg/kg/15 min) and then U-89232 (3 mg/kg/15 min) were infused before the 60 min of ischemia. Saline-treated animals served as controls (CON). Hemodynamic parameters were continuously monitored. Regional contractile wall function was quantified with ultrasonic crystals aligned to measure wall thickening. At the end of the protocol, infarct size (IS, as percentage of risk region) was determined by incubating the myocardium with p-nitrobluetetrazolium. With comparable myocardium at risk, infusion of U-89232 before 60 min of LADCA occlusion significantly reduced infarct size (IS, 18.5 +/- 3.7%; p < 0.001 vs. 63.2 +/- 3.3% for the controls), whereas glibenclamide had no effect on infarct size (IS, 69.5 +/- 4.4%). The administration of glibenclamide before U-89232 infusion blocked the infarct size-reducing effect of U-89232 [IS, 61.2 +/- 9.1 (NS) vs. controls and p < 0.001 vs. U]. Infusion of U-89232 had no effect on hemodynamic parameters or on regional wall function. At least in a pig model, U-89232 appears to be a cardioselective KATP channel opener, because in the absence of hemodynamic alterations, it exhibits a profound cardioprotective effect, which is fully reversible by blocking KATP channels.
We compared the effect of inotropic interventions (isoproterenol and pimobendan) and the relation between Ca2+ and isometric twitch force in atrial muscle from control rats and rats that had consumed alcohol for 2 months. At extracellular Ca2+ concentrations of 1-4 mM, alcohol atria developed less force than the controls. The median effective concentration (EC50) for extracellular Ca2+ was 3.2 +/- 0.01 mM for the alcohol group and 2.8 +/- 0.001 mM for the control group, whereas at maximal Ca2+, developed force was the same in both groups. To test whether the myofilament response to Ca2+ is altered with chronic alcohol consumption, we measured the relation between Ca2+ and force of atrial fiber bundle preparations extracted with Triton X-100. The Ca2+-force relation of alcohol atria (EC50 = 2.4 +/- 0.001 microM) was significantly shifted to the right of that of the control atria (EC50 = 1.94 +/- 0.001 microM Ca2+). Compared with controls, the alcohol atria demonstrated a significant depression in the inotropic effect of the beta-adrenergic agonist isoproterenol over a broad concentration range (10(-9)-10(-6) M). We also tested the effect of pimobendan, an inotropic agent with both phosphodiesterase-inhibiting and myofilament Ca2+-sensitizing actions. Developed force at concentrations of pimobendan <75 microM was similar between groups. However, at concentrations of pimobendan >75 microM, the developed force in alcohol atria was significantly less than control. Our results indicate that 2 months of alcohol consumption is associated with decreases in myofilament Ca2+ sensitivity and altered responsiveness to different inotropic agents.
The effect of neuraminidase treatment on the antigenicity of sarcoma I (Sal) and mastocytoma P-815-X2 cells was compared, both in terms of their reaction with various antisera (C57BL/6 anti-SaI, C57BL/6 anti-mastocytoma, rabbit and horse ALS) and complements (guinea pig, rabbit) or with sensitized lymphocytes (C57BL/6 anti-SaI, C57BL/6 anti-mastocytoma, A anti-mastocytoma). With sensitized lymphocytes the reactivity of neuraminidase-treated tumor cells was similar to that of nontreated cells. In contrast, after neuraminidase treatment, the tumor cells showed increased specific lysis with the antisera and complement. Rabbit complement was highly cytotoxic to the neuraminidase-treated cells but this nonspecific activity could be removed by absorption with agar or agarose. The results of this study would strongly suggest that neuraminidase treatment does not change the antigenic determinants of tumor cells but increases their interaction with complement after removal of negatively charged sialic acids.
A strain of Synechococcus sp. strain PCC 7942 with no functional Fe superoxide dismutase (SOD), designated sodB-, was characterized by its growth rate, photosynthetic pigments, and cyclic photosynthetic electron transport activity when treated with methyl viologen or norflurazon (NF). In their unstressed conditions, both the sodB- and wild-type strains had similar chlorophyll and carotenoid contents and catalase activity, but the wild type had a faster growth rate and higher cyclic electron transport activity. The sodB- was very sensitive to methyl viologen, indicating a specific role for the FeSOD in protection against superoxide generated in the cytosol. In contrast, the sodB- mutant was less sensitive than the wild type to oxidative stress imposed with NF. This suggests that the FeSOD does not protect the cell from excited singlet-state oxygen generated within the thylakoid membrane. Another up-regulated antioxidant, possibly the MnSOD, may confer protection against NF in the sodB- strain. These results support the hypothesis that different SODs have specific protective functions within the cell.
In search for the cellular and molecular basis for differences in aluminum (Al) resistance between maize (Zea mays) cultivars we applied the patch-clamp technique to protoplasts isolated from the apical root cortex of two maize cultivars differing in Al resistance. Measurements were performed on protoplasts from two apical root zones: The 1- to 2-mm zone (DTZ), described as most Al-sensitive, and the main elongation zone (3-5 mm), the site of Al-induced inhibition of cell elongation. Al stimulated citrate and malate efflux from intact root apices, revealing cultivar differences. In the elongation zone, anion channels were not observed in the absence and presence of Al. Preincubation of intact roots with 90 microM Al for 1 h induced a citrate- and malate-permeable, large conductance anion channel in 80% of the DTZ protoplasts from the resistant cultivar, but only 30% from the sensitive cultivar. When Al was applied to the protoplasts in the whole-cell configuration, anion currents were elicited within 10 min in the resistant cultivar only. La3+ was not able to replace or counteract with Al3+ in the activation of this channel. In the presence of the anion-channel blockers, niflumic acid and 4, 4'-dinitrostilbene-2, 2'disulfonic acid, anion currents as well as exudation rates were strongly inhibited. Application of cycloheximide did not affect the Al response, suggesting that the channel is activated through post-translational modifications. We propose that the Al-activated large anion channel described here contributes to enhanced genotypical Al resistance by facilitating the exudation of organic acid anions from the DTZ of the maize root apex.
Surface-sensitive X-ray absorption fine structure (XAFS) with sub-monolayer sensitivity based on grazing-incidence fluorescence detection is reported. The efficiency of fluorescence detection increased by more than two orders of magnitude by combining a multipole wiggler with a multi-element Si(Li) solid-state detector. The capability of the present technique for structural studies of surfaces and buried interfaces in the hard X-ray region was demonstrated by As K-edge XAFS studies of the InP(001) surface exposed to AsH(3) flow. The results indicated that ~0.1 monolayer As atoms are incorporated into the surface replacing the P atoms.
A simple enzyme-linked immunosorbent assay has been developed for quantitating the rabbit IgG present on the surface of sensitized red blood cells. A suitable cell lysis was carried out by an alkaline buffer, which dissolved the erythrocytes without forming any precipitate and without disruption of IgG, and facilitated the dissociation of the immune complexes, i.e. the erythrocyte-anti-erythrocyte rabbit IgG. In this alkaline buffer of pH 11.4 the IgG adsorbed directly into wells of microtitration plates unprecoated with anti-rabbit IgG. The detection was performed with alkaline phosphatase-conjugated goat anti-rabbit IgG and p-nitrophenyl phosphate as substrate. Constructing a calibration curve from rabbit IgG made possible the calculation of molecules of IgG bound per red cell. The method was sensitive for the detection of fewer than 500 bound IgG molecules per erythrocyte.
Ro 15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1,4]benzodiazepine-3-carboxylate), a partial inverse agonist of brain benzodiazepine receptors, has been shown to antagonize some actions of ethanol. In addition to conventional benzodiazepine binding sites, Ro 15-4513 binds to a specific cerebellar protein, the binding of which has been shown to be insensitive to diazepam. The binding of [3H]Ro 15-4513 was studied in washed membranes of the cerebellum, hippocampus, and cerebral cortex of two rat lines developed for differences in their sensitivity to ethanol-induced motor impairment. Only minor differences were found in the estimated parameters (KD and Bmax) for the total specific binding between the rat lines. The main difference between the rat lines was, however, observed in the characteristics of the cerebellar binding, all of which was displaced by diazepam in most of the alcohol-sensitive [alcohol-nontolerant (ANT)] rats, in contrast to only approximately 75% displacement in most of the alcohol-insensitive [alcohol-tolerant (AT)] ones. The following cerebellar results were obtained with the major subgroups of both lines, i.e., with the AT rats chosen for the presence of the diazepam-insensitive binding and with the ANT rats chosen for its absence. The KD for the total specific [3H]Ro 15-4513 binding in the ANT animals was about half of that in the AT animals. No line difference was found in the Bmax of the binding in these rats. Photolabeling with [3H]Ro 15-4513 showed that the diazepam-insensitive binding was in a protein with a molecular weight of 55,000.(ABSTRACT TRUNCATED AT 250 WORDS)
The biological activities of maitotoxin are strictly dependent on the extracellular calcium concentration and are always associated with an increase of the free cytosolic calcium level. We tested the effects of voltage-sensitive calcium channel blockers (nicardipine and omega-conotoxin) on maitotoxin-induced intracellular calcium increase, membrane depolarization, and inositol phosphate production in PC12 cells. Maitotoxin dose dependently increased the cytosolic calcium level, as measured by the fluorescent probe fura 2. This effect disappeared in a calcium-free medium; it was still observed in the absence of extracellular sodium and was enhanced by the dihydropyridine calcium agonist Bay K 8644. Nicardipine inhibited the effect of maitotoxin on intracellular calcium concentration in a dose-dependent manner. The maitotoxin-induced calcium rise was also reduced by pretreating cells with omega-conotoxin. Pretreatment of cells with maitotoxin did not modify 125I-omega-conotoxin and [3H]PN 200-110 binding to PC12 membranes. Nicardipine and omega-conotoxin inhibition of maitotoxin-evoked calcium increase was reduced by pertussis toxin pretreatment. Maitotoxin caused a substantial membrane depolarization of PC12 cells as assessed by the fluorescent dye bisoxonol. This effect was reduced by pretreating the cells with either nicardipine or omega-conotoxin and was almost completely abolished by the simultaneous pretreatment with both calcium antagonists. Maitotoxin stimulated inositol phosphate production in a dose-dependent manner. This effect was reduced by pretreating the cells with 1 microM nicardipine and was completely abolished in a calcium-free EGTA-containing medium. The findings on maitotoxin-induced cytosolic calcium rise and membrane depolarization suggest that maitotoxin exerts its action primarily through the activation of voltage-sensitive calcium channels, the increase of inositol phosphate production likely being an effect dependent on calcium influx. The ability of nicardipine and omega-conotoxin to inhibit the effect of maitotoxin on both calcium homeostasis and membrane potential suggests that L- and N-type calcium channel activation is responsible for the influx of calcium following exposure to maitotoxin, and not that a depolarization of unknown nature causes the opening of calcium channels.
A case of allergic contact dermatitis from miconazole is reported. Patch testing with a series of azole antimycotics was positive only to miconazole, isoconazole, tioconazole and oxiconazole. Those reacting are all beta-substituted 1-phenethyl imidazoles with an ortho-chlorine substitution on the aromatic ring. For this hitherto unreported pattern of cross-sensitivity, the designation of "ortho-chloro cross-sensitivity" is proposed.
The aim of this study was to identify the chemicals responsible for the sensitivity of a 44-year-old woman to her own perfume, but showing negative patch test results to the fragrance mix. For this purpose, the perfume concentrate from the eau de toilette was chemically fractionated. Each fraction obtained was afterwards tested on the patient using a ROAT and/or a patch test. Only 1 fraction gave a positive ROAT result. This fraction was analyzed and found to contain coumarin and ethyl vanillin. Coumarin, one of the most widely used fragrance compounds that is not present in the fragrance mix, was confirmed as being the sensitizer.