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Biomedical subjects

T Simon

Publications and source records attributed to T Simon.

At least 55 records · Page 3Linked to original sources
PubMed1992

Polymorphism of dextromethorphan metabolism: relationships between phenotype, genotype and response to the administration of encainide in humans.

The polymorphism of dextromethorphan and encainide metabolism is genetically determined and is related to the activity of hepatic CYP2D6. In order to examine the relations between CYP2D6 phenotype, genotype and the electrocardiographic response to the oral administration of encainide, 110 healthy subjects were studied. Metabolic ratios were calculated in urine after oral administration of 40 mg of dextromethorphan and in plasma obtained 2.5 h after oral administration of 50 mg of encainide. Encainide-induced electrocardiographic changes were measured 2.5 h after oral administration of the drug. Genotype was determined in 52 subjects. Results showed that phenotype, either extensive or poor metabolizer, for CYP2D6-dependent metabolism could be identified from the dextromethorphan metabolic ratio calculated in urine, from the encainide metabolic ratio calculated in plasma and from the genotype. However, despite the fact that the changes in atrioventricular (PR) and intraventricular (QRS) conduction times produced by encainide were different in extensive and poor metabolizer subjects and correlated with CYP2D6 activity, the electrocardiographic response was never 100% specific and sensitive for the identification of either phenotype. Moreover, genotypic identification of heterozygous and homozygous extensive metabolizer subjects did not predict CYP2D6 activity, as determined by dextromethorphan and encainide metabolic ratios, or encainide response, as determined by intraventricular and atrioventricular changes. Thus, CYP2D6 activity does not fully predict the electrocardiographic effects of encainide, and genotype, as determined in our study, cannot replace the determination of metabolic ratio in predicting CYP2D6 activity and encainide response in extensive metabolizer subjects.

Adult↗
PubMed1992

[Establishment of reference values for fructosamine and HbA1c in childhood].

Reference values for fructosamine and glycated haemoglobin in children are still lacking. Using samples from 522 children (age range 1 day to 9 years), plasma electrophoresis was performed, fructosamine and total protein were determined in EDTA-plasma, and glucose and the fraction of glycated haemoglobin (HbA1c) were determined in EDTA blood. The results were grouped according to age (1, 3 and 5 days, 6-28 days, 2-12 months, 2-3 years, 4-6 years, and 7-9 years). Differences between the age groups were determined using the Mann-Whitney-U-test, and the values in each group were summarized where possible. The 95%-interval was calculated for fructosamine, protein-corrected fructosamine, and HbA1c.

Child↗
PubMed1991

[Changes in the knowledge and attitude of physicians and health professionals in relation to AIDS during 1988-1990].

The authors interviewed in 1988, 570 and in 1990 425 health personnel about their knowledge and attitudes with AIDS. The results of 1990 survey shows: 63-76% of subjects changed their working habits, the increase rate to 1988 data is 30-40% and 11.7-18.0% changed their habits in their private life, the rate of increasing are: 8-9%. The safety gloves was mentioned by 82.1%-20% more than in 1988. 14% of the interviewed doctors and other health workers are refuse the care of an AIDS or a HIV positive patient, this rate is the double than was in 1988. Among the information resources the rate of postgraduate education was by 10% lower and 95% of the interviewed persons nominated the mass media as a main information channel in their knowledges about AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin.

Increasing evidence suggests an immunoregulatory function of the potent steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) which has been successfully applied for treatment of psoriasis. The skin is both a site of production and a target of 1,25(OH)2D3. In vitro, 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of keratinocytes. We investigated the in situ expression of vitamin D-receptors (VDR) in normal and psoriatic skin by immunochemical methods. The VDR were visualized using the monoclonal antibody (MoAb) 9A7g to the VDR and the labeled avidinbiotin technique. Immunoreactivity was consistently confined to nuclei in all skin biopsies. In normal skin specimens (n = 10) VDR antigens were expressed in keratinocytes of all epidermal layers (except those of the stratum corneum) and in cells of the epidermal appendages. Double labeling experiments with MoAb to cluster-defined antigens indicated that melanocytes and approximately 75% of Langerhans cells exhibit 1,25(OH)2D3 receptors in normal skin biopsies (n = 5). Depending on their localization in skin compartments 42-62% of CD11b+ positive macrophages and 45-75% of CD3+ T lymphocytes expressed VDR. Non-lesional psoriatic skin specimens (n = 8) revealed nearly identical staining patterns. Lesional psoriatic skin specimens (n = 8) exhibited a significant increase of VDR expression both in basal and suprabasal epidermal layers as measured by computer-assisted morphometry and showed a remarkable change of the immune cell pattern: the densitity and proportion of VDR positive T lymphocytes and macrophages were higher in the epidermal and the perivascular papillary loop compartment. These in vivo findings strongly support the hypothesis that 1,25(OH)2D3 modulates immune response and cell proliferation/differentiation in human skin.

Adult↗
PubMed1990

Antibody domain mutants demonstrate autonomy of the antigen binding site.

We have constructed derivatives of a lambda I light chain-bearing anti-(4-hydroxy,3-nitrophenyl)acetyl (NP) antibody which have the V regions exchanged between heavy chains and light chains of the kappa or lambda I type. These antibodies are assembled and secreted normally, and bind haptenic and macromolecular ligands like the wild-type; similar results are obtained for monovalent heterodimers of VHCL and lambda I light chains. The observed independence of the binding site from the constant region context argues against a role of longitudinal interactions between constant and variable domains in antigen recognition, and therefore against cooperativity between binding sites.

Animals↗
PubMed1990

[New methods for the morphometric analysis of anisotropic tissues].

Some unbiased, design-based stereological methods that have recently been developed for the study of anisotropic tissues like muscle, myocardium, brain, cartilage, and skin, are briefly reviewed. Vertical sections permit the unbiased estimation of surface density and mean volume-weighted particle volume from microscopic sections. The available experience includes various studies on malignant melanomas. In addition, the surface area of total organs (e.g., the pleural surface area) can be determined with vertical sections, which was hitherto not feasible. The orientator is a simple method to generate isotropic sections in biological material. With the orientator method it is possible to determine not only the surface density, but also the length density of the objects. Thus the method is suitable for the study of fascicular systems (tubules etc.), and for the study of vascularisation in particular.

Animals↗
PubMed1989

Anti-inflammatory drugs in experimental atherosclerosis. 7. Spontaneous atherosclerosis in WHHL rabbits and inhibition by cortisone acetate.

The Watanabe heritable hyperlipidemic (WHHL) rabbit, an animal model for familial hypercholesterolemia, has a deficiency in low density lipoprotein (LDL) receptor binding and exhibits elevated plasma lipoprotein levels and spontaneous atherosclerosis. Since atherosclerotic plaque formation has a number of features in common with the inflammatory process, we have investigated the effect of dietary supplementation with an anti-inflammatory steroid (cortisone acetate, 5 mg daily for 3 months) on atherosclerosis using the WHHL rabbit as a model. Atherosclerotic plaque formation in cortisone-fed animals was reduced by about 60% compared to control WHHL rabbits. Steroid administration increased circulating cholesterol levels modestly and triglycerides were increased about 6-fold. While very low density lipoprotein (VLDL)-cholesterol was increased, LDL-cholesterol levels were decreased and the particle was more triglyceride-enriched as well as less dense. Steroid-fed animals also exhibited decreased platelet aggregation and increased aortic 15-lipoxygenase activity. The histological observations showed typical fibrous plaques in aortas of both control and cortisone-fed rabbits, with intima thickened by foamy macrophages and subcellular lipoproteinaceous debris covered by a fibrous cap. These findings thus indicate that steroids reduce the rate of plaque initiation or progression but do not significantly change the histological appearance of the lesion.

Animals↗
PubMed1988

Hydroxyurea and etoposide: in vitro synergy and phase I clinical trial.

L1210 murine leukemia cells were treated with hydroxyurea (10-200 microM) for 24 hours and/or etoposide (0.17-3.4 microM) for 2 hours. Combination treatments used a fixed molar hydroxyurea:etoposide ratio of 58.9:1, and drug-drug interactions were quantitated according to the median effect principle. Hydroxyurea and etoposide were antagonistic at low doses at which the survival fraction was greater than 0.5 and synergistic at higher doses at which the survival fraction was less than 0.25. In a phase I clinical trial, 19 patients were treated with the two drugs at one of three dose levels. The dose-limiting toxic effect was myelosuppression. Doses of 100 mg of etoposide/m2 per day by continuous infusion and 500 mg of hydroxyurea orally every 4 hours, both for 3 days, are recommended for phase II trials.

Adult↗
PubMed1988

Modulation of antibody binding affinity by somatic mutation.

The affinity of hapten binding of monoclonal antibodies (MAbs) specific for 4-hydroxy-3-nitrophenylacetyl (NP) has been investigated at the molecular level by both site-specific mutagenesis and recombinant antibody construction, followed by expression in myeloma cells. We have shown that a single point mutation (trp----leu at codon 33) in the variable region of the heavy chain (VH) is sufficient to endow a primary-response, germline-encoded antibody with an affinity for antigen typical of a secondary-response antibody carrying the same mutation. We have also demonstrated that mutations additional to the trp----leu exchange in the heavy chain and further mutations in the light chain are irrelevant to the high-affinity phenotype of secondary-response antibodies. Since some of these are "parallel" mutations common to clonally unrelated antibodies, this suggests that the mutation rate is not constant across the entire immunoglobulin variable region. Although antibodies with a trp----leu exchange at position 33 are positively selected because of improved hapten binding affinity, we have found that, under rare circumstances, other patterns of mutations may be selected through particular D-JH combinations; we have demonstrated one case where this has generated an antibody with very efficient hapten binding ability.

Animals↗
PubMed1988

Antibody engineering for the analysis of affinity maturation of an anti-hapten response.

The influence of structural variation, previously observed in a panel of V186.2 VH/V lambda 1-expressing anti-NP antibodies from the secondary response, on the affinity of these antibodies was examined by site-specific mutagenesis and recombinant antibody construction. A tryptophan----leucine exchange at position 33 in the VH segment of all but one of the high-affinity antibodies is the most frequently observed somatic mutation and by itself leads to a 10-fold higher affinity; all other somatic exchanges are irrelevant for affinity selection. In the single case of a high-affinity antibody without this common exchange, high affinity is mediated by a combination of mutations (including a one-codon deletion) in VH and the particular D-JH rearrangement carried by this antibody. The data indicate that the pattern of somatic diversification through hypermutation is shaped by affinity selection, but that only a single point mutation is available in the VH and the VL gene of lambda 1 chain-bearing anti-NP antibodies which by itself leads to an increase of hapten-binding affinity. Based on the analysis of two secondary response antibodies from which somatic mutations in VH and VL have been eliminated, it is also concluded that the recruitment of B cell clones into the pathway of hypermutation involves a mechanism which is not based upon affinity differences towards the antigen.

Amino Acid Sequence↗
PubMed1988

Interzonal and intrazonal heterogeneities in the renin status of the preglomerular arterioles in five species.

In five species (mouse, rat, rabbit, rhesus monkey and man) the renin status of the preglomerular arterioles was examined using two immunohistochemical methods: the measurement of the renin-positive portion of the vessels, reflecting the respective number of granulated cells, and the semiquantitative assessment of the renin concentration in the juxtaglomerular epithelioid cells with antibody dilution series. The main objective of the study was to compare the interzonal with the intrazonal internephron heterogeneities, i.e. the differences between the average renin status of the preglomerular arterioles in the superficial, intermediate and juxtamedullar cortex with the differences between the renin status of the individual afferent arterioles in one and the same cortex region. In contrast to small interzonal heterogeneities, substantial intrazonal differences in the renin status of the corresponding nephrons were found.

Animals↗
PubMed1988

Computer-assisted morphometric study of the innervation of the guinea pig heart.

A computer-assisted method is introduced for the morphometric analysis of immunoreactive markers of the innervation of the heart, such as synaptophysin, neuropeptide Y (NPY), neurotensin (NT), substance P (SP), and calcitonin gene-related peptide (CGRP). Video images of stained sections were digitalized and the area density (AD) of the immunoreactive structures was measured by discrimination for grey levels within the myocardium of the right atrium, the perivascular region of epicardial arteries, and the trunk of the bundle of His. Synaptophysin immunoreactivity (IR), which served as a marker for presynaptic vesicles, indicated a dense innervation of the conductive system (AD 1.5241). Marked differences in the pattern of distribution were found between the neuropeptides. The AD of NPY-IR (0.5073) and SP-IR (0.1352) was highest in the perivascular tissue, while NT-IR (0.1628) and CGRP-IR (0.5161) exhibited maximal values in the bundle of His. The computer-assisted morphometric measurement of the AD of immunoreactive markers is suggested to be a suitable method for quantitative studies of the innervation of the heart under normal and experimental conditions.

Animals↗
PubMed1988

A GABAergic mechanism in the posterior hypothalamus modulates baroreflex bradycardia.

Several laboratories have shown that electrical stimulation in the posterior hypothalamus inhibits the baroreceptor reflex. However, the results of these studies are difficult to interpret since it is not known if the attenuation of the baroreflex results from activation of axons of passage or from stimulation of hypothalamic cell bodies. The purpose of this study was to determine the effects of chemical stimulation of posterior hypothalamic neurons upon the baroreflex. Arterial baroreceptors were activated by increasing the pressure in an isolated carotid sinus in anesthetized cats and by an increased arterial pressure following intravenous injection of phenylephrine in both anesthetized cats and rats. The baroreceptor reflex was evaluated before and after a GABA antagonist (picrotoxin) was microinjected into the posterior hypothalamus. The bradycardia, but not the depressor response, elicited by increasing carotid sinus pressure was attenuated after unilateral microinjections of picrotoxin into the posterior hypothalamus. In addition, the heart rate response to a phenylephrine-evoked rise in arterial pressure was reduced after picrotoxin was microinjected in both the cats and the rats. Microinjection of a GABA agonist (muscimol) into the same hypothalamic site returned resting heart rate and arterial pressure to levels seen prior to picrotoxin. These results show that the depression of the bradycardia produced by hypothalamic stimulation results from activation of cell bodies in the posterior hypothalamus. This hypothalamic effect upon the baroreflex bradycardia may involve a GABAergic mechanism.

Animals↗