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Biomedical subjects

E Vogel

Publications and source records attributed to E Vogel.

At least 55 records · Page 3Linked to original sources
PubMed1994

Impaired TCR signal transduction, but normal antigen presentation, in a patient with common variable immunodeficiency.

We describe a 27-year-old white man with common variable immunodeficiency (CVID) who has two healthy histoidentical brothers and one IgA-deficient sister who shares one HLA haplotype with the patient. T cells from the patient with CVID showed an impaired response to recall antigens (tetanus toxoid, E. coli), whereas his IgA-deficient sister and his two healthy histoidentical brothers responded normally. Cross-mixing experiments using isolated monocytes and T cells from the CVID patient and one histoidentical brother revealed that the patient's monocytes were fully functional in processing and presenting antigen to resting T cells of his brother, and provided normal accessory cell function for superantigen-induced activation of his brother's resting T cells. In contrast, the patient's T cells were unable to respond to antigen presented by the brother's monocytes and failed to respond with an increase in intracellular free Ca++ to stimulation with superantigen, which is known to bind to the TCR V beta-chain outside the antigen-binding groove. However, stimulation with a combination of PMA and IM, directly activating protein kinase C and increasing intracellular free Ca++ by bypassing membrane receptors, induced normal Ca++ flux. These data indicate that the patient with CVID has a defect in TCR-mediated signalling at the level of the T cells which is not present in his histoidentical healthy brothers or in his haploidentical IgA-deficient sister.

Adolescent↗
PubMed1994

The costimulatory signal CD28 is fully functional but cannot correct the impaired antigen response in T cells of patients with common variable immunodeficiency.

A wide spectrum of different immunologic abnormalities have been postulated as being responsible for the impairment of specific antibody production and the decrease in all or selected immunoglobulin isotypes present in common variable immunodeficiency (CVID). These abnormalities include impaired B cell differentiation and/or function, defective macrophage function, and significant T cell defects. The aim of the present study was to delineate whether the accessory molecule CD28 is involved in the impaired antigen response of T cells from patients with CVID. Our results demonstrate that CD28 costimulation was functional in T cells stimulated with anti-CD3 or anti-TCR MoAb, but could not correct the impaired response of patients' peripheral blood T cells to tetanus toxoid. Analysis of patients' long-term cultured T cells further confirmed these results. Exogenous rIL-2, another costimulus, augmented but did not correct the defective proliferation and lymphokine production in patients' antigen-driven peripheral blood T lymphocytes or in long-term cultured T cells. These findings indicate that the CD28 signalling pathway in these patients' T cells is unimpaired, and that costimulation via CD28 cannot correct the defect occurring in the course of TCR-mediated T cell activation.

Adolescent↗
PubMed1994

Inhibition of receptor-dependent and receptor-independent generation of the respiratory burst in human neutrophils and monocytes by human serum IgA.

An important feature of the role of IgA in protection against infection and disease at the level of the mucosal surfaces might be the elimination of pathogens without induction of a strong inflammatory reaction. In the present study we addressed the question whether IgA has a regulatory effect on the generation of reactive oxygen intermediates in human neutrophils and monocytes (i.e. the respiratory burst). Cells were stimulated with heat-inactivated Haemophilus influenzae type b or phorbol myristate acetate, stimuli known to use different recognition structures or signal transduction pathways. Concentrations of IgA as low as 10 mg/L significantly inhibited the receptor-dependent Haemophilus influenzae-induced respiratory burst in granulocytes, as assessed by measuring luminol-enhanced chemiluminescence. Furthermore, IgA had a dose-dependent inhibitory effect on the receptor-independent induction of the respiratory burst, as examined by flow cytometry in monocytes and granulocytes activated with phorbol myristate acetate. Our results therefore indicate that inhibition of receptor-ligand interaction is not a sufficient explanation for the IgA-mediated modulation of the respiratory burst in human phagocytic cells. In addition, IgA might directly regulate the activation of the respiratory burst at the level or downstream of protein kinase C activation. By modulating the release of mediators of inflammation such as reactive oxygen intermediates, the inflammatory response could be down-regulated at the level of the mucosal surfaces, thereby preventing the development of sequelae of an exaggerated inflammatory response potentially leading to local or systemic pathology.

Adolescent↗
PubMed1994

Mechanism-based predictions of interactions.

Exposure to more than one toxic compound is common in real life. The resulting toxic effects are often more than the simple sum of the effects of the individual compounds. It is unlikely that it will ever be possible to test all combinations. It is therefore highly desirable to improve or develop means for reasonably approximating predictions of interactions. In order to be valid and extrapolatable, these predictions are most promising if they are mechanism-based. Examples will be given for possibilities of mechanism-based predictions of interactions which exceed trivialities of simple increases by enzyme induction of enzymatic rates of a given biotransformation pathway leading to a toxic metabolite. Instead, examples will be provided where competition between various enzymes for shunting the same substrate into divergent pathways can lead to predictable dramatic changes in toxicity by shifting the metabolic routes under conditions of no significant changes of overall metabolism. Further examples are given on predictable interactions between chemicals which need bioactivation for exerting their toxicity and chemicals which effect hormonal status and other endogenous factors which in turn modify enzymes involved in the control of toxic metabolites.

Animals↗
PubMed1993

Defective interleukin-2 and interferon-gamma gene expression in response to antigen in a subgroup of patients with common variable immunodeficiency.

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestations of the disease and in the underlying mechanisms leading to the immunodeficiency. The impairment of B-cell function can be due to an intrinsic defect of the B cells, a deficiency in the function of the antigen-presenting cell, or a dysfunction in the course of T-cell activation. In the present report we have focused our attention on T-lymphocyte activation in three patients with CVID. Numbers of T and B cells, as well as CD4 and CD8 T cell subsets, were within the normal range. The patients' B cells secreted IgM but did not secrete IgG and IgA in response to B-cell stimuli in vitro. Addition of allogeneic T cells was followed by an increase in IgM production but had no effect on the other immunoglobulin isotypes. Examination of T-cell function revealed impaired proliferative response, interleukin-2 (IL-2) and interferon-gamma gene expression and IL-2 release after antigenic stimulation, whereas T-cell proliferation, as well as IL-2 gene expression and release in response to stimulation via anti-CD3, were comparable to those of healthy control subjects. Anti-CD3-induced IFN-gamma gene activation in T cells from two patients was comparable to that of control subjects, whereas T cells from the third patient showed reduced expression of IFN-gamma mRNA. In contrast to the decreased IL-2 and IFN-gamma mRNA levels, IL-2R transcripts examined in parallel were normal in CVID T cells on stimulation with antigen. The defect in IL-2 and IFN-gamma mRNA expression after stimulation with antigen, but not with anti-CD3, suggests an abnormality confined to T-cell activation by the T-cell receptor.

Adult↗
PubMed1993

Tumour localisation kinetics of photofrin and three synthetic porphyrinoids in an amelanotic melanoma of the hamster.

In this study the localisation of porphyrinoid photosensitizers in tumours was investigated. To determine if tumour selectivity results from a preferential uptake or prolonged retention of photosensitizers, intravital fluorescence microscopy and chemical extraction were used. Amelanotic melanoma (A-Mel-3) were implanted in a skin fold chamber in Syrian Golden hamsters. Distribution of the porphyrin mixture Photofrin and three porphycenes, pure porphyrinoid model compounds, was studied quantitatively by intravital fluorescence microscopy. Extraction of tissue and blood samples was performed to verify and supplement intravital microscopic results. Photofrin accumulated in melanomas reaching a maximum tumour:skin tissue ratio of 1.7:1. Localisation of the different porphycenes was found to be highly tumour selective (3.2:1), anti-tumour selective (0.2:1), and non-selective (1:1) with increasing polarity of the porphycenes. The two non-tumour selective porphycenes had distinctly accelerated serum and tissue kinetics; serum halflife times being as short as 1 min. The specific localisation of the slowly distributed, tumour selective photosensitizers, occurred exclusively during the distribution from serum and uptake into tissues. For the most selective porphycene, the tumour selection process had a halflife of 260 +/- 150 min and led to a strongly fluorescent tumour edge edema. Accumulation of porphyrines by the amelanotic melanoma (A-Mel-3) can be attributed to an enhanced uptake rate for lipophilic molecules in this subcutaneously growing neoplasm. The slow distribution of the two tumour specific photosensitizers and the strong fluorescence of these hydrophobic molecules in the tumour compartment with a high water content indicate a carrier role of serum proteins in the selection process. Enhanced permeability of the tumour vasculature to macromolecules appears to be the most probable reason for the tumour selectivity of these two sensitisers.

Animals↗
PubMed1993

Asbestos-related radiographic abnormalities in elevator construction workers.

Elevator construction workers are exposed to asbestos dust during construction and refurbishment work on older buildings. We screened a cohort of workers, all with greater than 20 yr of employment in the industry, with clinical examinations, chest radiography ("B" reader interpretations), and routine spirometry. Twenty of the 91 workers (22%) had evidence of pleural disease, but none of them had an interstitial process consistent with asbestosis. Of those with pleural thickening, 15 had bilateral circumscribed plaques and five had unilateral plaque formation. There were no cases of diffuse pleural thickening, benign pleural effusions, or mesothelioma identified in our cohort. The difference in the mean body mass index of those with pleural abnormalities (29.18 +/- 3.95) and those without (27.7 +/- 3.86) was not statistically significant (p = 0.135). We conclude that elevator construction workers have an increased risk for the development of asbestos-related pleural disease.

Analysis of Variance↗
PubMed1992

Prolactin similar to ectopic pituitary isograft restores responsiveness in Snell dwarf mice.

The effects of ovine prolactin (PRL) (2 x 5 IU a day) and an ectopic pituitary isograft on the responsiveness were examined using locomotor and exploratory activities as measures in PRL-growth-hormone-thyrotropin-deficient Snell dwarf mice (dw/dw). After 5 weeks of treatment, both PRL and the graft restored the two behavioural measures to normal levels. Results clearly demonstrate the involvement of PRL in global behavioural responsiveness and suggest a possible role for PRL in the changes induced by the graft.

Animals↗
PubMed1991

[An epidural spinal abscess with caudal symptoms as a complication of Crohn's disease].

Progressive symptoms of caudal compression (flaccid paraparesis, sensory disorders), accompanied by severe pain and fever, developed over a few days in a 26-year-old man with Crohn's disease for 11 years. Spinal computed tomography, performed under the diagnosis of herniated disc, revealed intraspinal soft tissue, as well as gas in the spinal canal (L2-S3) and the paravertebral muscles. This led to the diagnosis of acute epidural abscess and a laminectomy was performed (at L4-S2). Intraspinally there was thickened, bluish fatty tissue; thick pus exuded between dura and the sacral roots. Suction-irrigation of the spinal canal was undertaken via an epidural drain. Postoperative contrast infusion into the colon demonstrated a fistula directed towards the sacrum. The postoperative course was complicated by severe respiratory impairment of which the patient died.--Epidural abscess is a rare complication of Crohn's disease. Because of its poor prognosis early diagnosis with magnetic resonance imaging or computed tomography should be undertaken in every patient with Crohn's disease who has back pain, fever or, particularly, symptoms of spinal compression.

Abscess↗
PubMed1991

Comparison of the behavioural effects of an adenosine A1/A2-receptor antagonist, CGS 15943A, and an A1-selective antagonist, DPCPX.

CGS 15943A is the first reported nonxanthine adenosine antagonist and it shows high affinity towards A1 and A2 receptors. The present data show that CGS 15943A increased in a dose-dependent manner locomotor activity of mice confronted with a free exploratory test without markedly modifying rears or, at low or medium doses, novelty seeking responses. In the light/dark choice procedure, which is especially appropriate for revealing anxiolytic and anxiogenic drug-effects, CGS 15943A decreased the time spent by mice in the lit box and increased the number of transitions. By contrast, the highly selective adenosine A1 receptor, DPCPX, did not significantly modify the behavior of mice except at high doses, which decreased it in the free exploratory test. It is suggested that the present findings confirm the hypothesis that the behavioral effects of adenosine antagonists are linked to their actions at adenosine A2 receptors.

Adenosine↗
PubMed1991

Behavioral effects of rolipram and structurally related compounds in mice: behavioral sedation of cAMP phosphodiesterase inhibitors.

The behavioral effects of specific cAMP phosphodiesterase inhibitors (PDE-I) such as rolipram and structurally related compounds were investigated in mice. Selected PDE-I induced a potent dose-dependent decrease in locomotion and in rearing of mice confronted with a free exploratory procedure, these effects being considered as a behavioral sedation. However, in the light/dark choice test especially conceived to reveal disinhibitory and/or anxiolytic action, they did not show obvious effects. These results suggest that the increase of cAMP probably does not account for our previously observed anxiolytic properties of BW A78U, an adenine derivative PDE-I (20).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

m-Chlorophenylpiperazine enhances neophobic and anxious behaviour in mice.

1-(3-Chlorophenyl)piperazine (mCPP) reduced novelty-seeking behaviour as well as the number of rears in mice confronted with a free exploratory test. Moreover, mCPP was found to decrease the time spent by mice in the lit box and the number of transitions in a two-box light/dark choice situation validated for the detection of anxiolytic or anxiogenic drugs. These results suggest that mCPP enhances emotional responses towards novel and aversive places. Since mCPP has been reported as a 5-HT1C receptor agonist, it can be hypothesized that increased activity of serotonin may play a role in regulating certain forms of emotional behaviour in animals.

Analysis of Variance↗
PubMed1990

Serenics fluprazine (DU 27716) and eltoprazine (DU 28853) enhance neophobic and emotional behaviour in mice.

Two tests designed to elicit responses to novelty and to aversive stimuli were used to study the effects of the serenics fluprazine and eltoprazine on the behaviour of male Swiss mice: a free exploratory test (fluprazine; 2.5, 5 and 10 mg/kg; eltoprazine: 2.5, 5, 10 and 15 mg/kg) and a two-box choice procedure (fluprazine: 1.25, 2.5, 5 and 7.5 mg/kg; eltoprazine: 2.5, 5, 7.5 and 10 mg/kg). Both drugs increased the neophobic reaction, as well as the avoidance of a brightly illuminated box. These effects closely resemble those of psychostimulant drugs such as methamphetamine and caffeine. It is hypothesized that the behavioural changes induced by these drugs may be due to a nonspecific increase of the emotional reactivity of animals.

Animals↗
PubMed1990

Anxiolytic and sedative properties of BW A78U, a novel anticonvulsant adenine derivative.

The anticonvulsant BW A78U, tested in a free mouse exploratory situation, reduced in a dose-dependent fashion the locomotion and the number of rearings, this sedative effect being significant up to a dose of 15 mg/kg (IP, 20 min before testing). In an unconditioned conflict test, the light/dark box choice situation, specific for anxiolytics, low doses of BW A78U increased the time spent by mice in the lit box as well as the number of transitions between the two boxes. Finally, we demonstrated that this drug was able to protect mice against pentylenetetrazole-induced convulsions. Our data show that BW A78U possesses some of the characteristic properties of the minor tranquilizers. However, since this compound binds to the benzodiazepine receptor with a very low affinity (IC50 = 13.6 microM), it can be assumed that this drug does not exert its behavioral effects through these receptors. It may interfere with other targets involving adenosine, another potent physiological regulator of neuronal excitability.

Animals↗
PubMed1990

Anxiogenic effects of a benzodiazepine receptor partial inverse agonist, RO 19-4603, in a light/dark choice situation.

In a light/dark choice procedure, the imidazothienodiazepinone RO 19-4603, given alone, induced a dose-dependent decrease in the time spent by mice in the lit box as well in the number of transitions between the two boxes. These data confirm the anxiogenic intrinsic properties of inverse agonists of the benzodiazepine receptor. Since RO 19-4603 also reversed the anxiolytic effects of ethanol and exhibited proconvulsant properties, it is suggested that the antagonistic action of this drug against ethanol could be due to an additive rather than an interactive process.

Animals↗
PubMed1990

Alcohol exposure before pregnancy: biochemical and behavioral effects on the offspring of rats.

The effect of maternal alcohol exposure before mating was investigated in the offspring over a period of 6 months concerning some specific aspects of energy metabolism in the brain and the liver. The following biochemical parameters were analyzed: superoxide dismutase (involved in elimination of free radicals produced during ethanol oxidation), enolase isoenzymes (markers of nerve cell maturation), and alcohol and aldehyde dehydrogenase (the main alcohol degradating enzymes). These enzymatic activities were measured at their subcellular level. In these animals never directly exposed to alcohol, superoxide dismutase activity was decreased mainly in the liver cytosol. Only the nonneuronal form of enolase activity was modified. Alcohol dehydrogenase was decreased in the liver as well as in the brain. Aldehyde dehydrogenase was also decreased in the liver and in the brain, mainly in the mitochondria. Behavioral observations showed decreased emotional reactivity as well as an increase in locomotor activity. Our results suggest that long-lasting biochemical and behavioral effects of alcohol may occur in the offspring starting at the earliest stage of development.

Animals↗