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Biomedical subjects

M Langlois

Publications and source records attributed to M Langlois.

At least 55 records · Page 3Linked to original sources
PubMed1997

Distribution of lymphocyte subsets in bone marrow and peripheral blood is associated with haptoglobin type. Binding of haptoglobin to the B-cell lectin CD22.

Haptoglobin is an acute phase protein showing a genetic polymorphism with 3 major types: Hp 1-1, Hp 2-1, and Hp 2-2. In this study, flow cytometric analysis demonstrated that all three haptoglobin types bind to CD22 on human B-lymphocytes with equal affinity. Comparison of reference values for lymphocyte subsets in peripheral blood and bone marrow showed significant differences between haptoglobin types. Haptoglobin 2-2 is associated with higher peripheral B-lymphocyte counts (P < 0.001) and CD4+ T-lymphocyte counts (P < 0.05). In bone marrow, CD4+ T-cell percentages were highest (P < 0.001) but B-cell percentages were lowest (P < 0.001) in haptoglobin 2-2 type. A negative correlation between serum haptoglobin 1-1 concentration and peripheral B-cell counts was observed (r = -0.663). Our results suggest that haptoglobin is involved in lymphocyte distribution. The present findings are a potential cause of over- or underestimation of lymphocyte subset counts in the clinical staging of immunodeficiency diseases.

Adult↗
PubMed1996

Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors.

Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.

Amides↗
PubMed1996

Structure-activity relationships for substrates and inhibitors of pineal 5-hydroxytryptamine-N-acetyltransferase: preliminary studies.

Tryptamine, (1-naphthyl)ethylamine and phenethylamine derivatives were tested as substrates of ovine pineal serotonin-N-acetyl transferase (5-HT-NAT), a key enzyme involved in the synthesis of melatonin. Almost all of the indole derivatives possessed affinity similar to that of tryptamine (Km = 0.05 mM), while the substituted naphthalene and phenyl derivatives were less potent. However, the Km values seem be influenced by the steric hindrance and polar properties of the substituent. Vmax values for the naphthyl and phenyl derivatives were generally 10-20-fold higher than those of the indole derivatives and no clear structure-activity relationship was observed. Melatonin and several bioisosteric derivatives were shown to be inhibitors of 5-HT-N-acetyltransferase. Preliminary data suggested that over the 5-50-microM concentration range, melatonin was a competitive inhibitor (IC50 = 10 microM) with a concentration-dependent inhibitory effect on its own synthesis in the pineal gland. However, the bioisosteric naphthalene derivatives were characterized instead as mixed inhibitors. (1-Napthyl)ethylacetamido, a putative melatoninergic antagonist, was also shown to be an inhibitor of 5-HT-N-acetyltransferase (IC50 = 8 microM) and is a promising tool for the regulation of melatonin synthesis and the understanding of its role.

Acetylation↗
PubMed1995

Design and synthesis of new naphthalenic derivatives as ligands for 2-[125I]iodomelatonin binding sites.

New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-[125I]iodomelatonin as the radioligand. Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor (Ki = 8 +/- 0.2 nM) for N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]propionamide (4b) (Ki = 0.67 +/- 0.05 nM) and N-[2-(2,7-dimethoxynaphthyl)ethyl]cyclopropylformamide (Ki = 0.05 +/- 0.004 nM) (4k). Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2. The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-gamma-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.

Animals↗
PubMed1993

Structural analysis by the comparative molecular field analysis method of the affinity of beta-adrenoreceptor blocking agents for 5-HT1A and 5-HT1B receptors.

The affinities of 17 beta-adrenoreceptor antagonists for 5-HT1A and 5-HT1B receptors were evaluated in binding assays. A large range of Ki values (2-10,000 nM) was observed and ortho or meta substitution of the aromatic ring carrying the amino chain was implicated in the high affinity Ki values, whereas para substitution elicited a dramatic drop in activity. These variations were analyzed with two molecular design tools: the active analogue approach (AAA) and the new 3D-QSAR (quantitative structure activity relationship) method, comparative molecular field analysis (CoMFA). The AAA method emphasized, by superimposition of selected conformations of the molecules, the favorable and unfavorable volumes implicated in the receptor recognition. CoMFA generated a linear expression between the biological data and the different values of electrostatic and steric fields surrounding the molecules. It predicted the values of selected molecules but also those of new molecules not included in the study. The excellent accuracy of the prediction revealed the potential of the method for the design of new compounds. CoMFA demonstrated the important contribution of steric parameters, evaluated at 92%, compared to the electrostatic field (evaluated at 8%) to explain the affinity for 5-HT1A and 5-HT1B receptors. This study emphasizes also the importance of the occupancy of a hydrophobic pocket in the receptor site located near the area interacting with the aromatic moiety, and subsequently its use for the design of new, potent, specific antagonists of 5-HT1A and 5-HT1B receptors.

Adrenergic beta-Antagonists↗
PubMed1993

The immunophenotype of Ewing's sarcoma. An immunohistochemical analysis.

Since 1963, 53 cases of Ewing's sarcoma have been diagnosed at the N. Goormaghtigh Institute of Pathological Anatomy. All tumours were classified according to their growth pattern as described by Kissane: diffuse, lobular or organoid, the latter with pseudorosettes, or belonging to the fillagree type. In 45 cases, an immunohistochemical examination was carried out on routinely processed material in order to determine the immunophenotype of the tumours and to get more information on the histogenesis of the tumours. Antibodies against cytokeratin, desmin, vimentin, neurofilaments, neuron-specific enolase, Leu7, synaptophysin, chromogranin, the muscle-specific actin, the Von Willebrand factor and the common leucocyte antigen were used in a biotin-streptavidin procedure. The presence of neural markers such as neuron-specific enolase, synaptophysin and Leu7 was proved in the majority of the cases. The expression of the three markers was absent in only two cases. Neurofilaments were demonstrated to be present in 5 of the 6 cases for which fresh material was available. The results of this study point towards a possible neuroectodermal origin of Ewing's sarcoma. This is in agreement with the results of cell culture experiments and of cytogenetic studies.

Adolescent↗
PubMed1993

Cross-resistances to antiviral drugs of IUdR-resistant HSV1 in rabbit keratitis and in vitro.

The emergence of cross-resistance to various antiviral drugs was investigated both in vivo and in vitro for herpes simplex virus type 1 (HSV1) resistant to idoxuridine (IUdR 0.24%) obtained by seven successive passages (from P0 to P7) in rabbit keratitis treated by IUdR. The viral population obtained at the seventh IUdR passage (P7) showed an activity of the thymidine kinase (TK) reduced to 5.6% of the parental strain (PO); moreover, most of the clones of P7 showed an altered TK phenotype determined by the [125I]iododeoxycytidine (IDC) procedure. In rabbit keratitis, IUdR-resistant viral population P7 showed cross-resistance to bromovinyl desoxyuridine (BVDU) (0.5%) and to acyclovir (ACV) (3%). Under trifluorothymidine (1%) treatment, P7 showed an intermediate sensitivity. HSV1 at P7 remained sensitive to adenine arabinoside (Ara A) (3%) and to dihydroxy-propoxymethylguanine used at high concentration (3%). The in vitro sensitivity determination to various antiviral drugs was investigated by dye-uptake assay for the initial viral population PO and for HSV1 collected under IUdR treatment at the third (P3) and the seventh (P7) passages. Cross-resistance to TK-dependent drugs, such as IDC, BVDU, and ACV were found at P7. P7 remained sensitive to Ara A and to phosphonoformic acids antiviral drugs known not to be dependent on viral TK.

Animals↗
PubMed1993

The prognostic significance of the DNA content in Ewing's sarcoma: a retrospective cytophotometric and flow cytometric study.

The DNA content of the cell nuclei of Ewing's sarcoma was analysed by means of cytophotometry in situ with image analysis in Feulgen-stained sections in 37 patients, and by retrospective flow cytometry according to the method of Hedley in 26 patients. Different histogram patterns were obtained: normal unimodal or bimodal DNA distributions and abnormal DNA distributions with one or two stem lines, or an abnormal DNA distribution with no stem lines. Both methods enabled us to make a distinction between two groups of Ewing's sarcomas with a different prognosis. All patients with aneuploid tumours died within 5 years after the initial diagnosis. Eleven of 19 (58%) patients with a normal DNA distribution in their tumour, as determined by cytophotometry, are still alive and in good health with a mean survival period of 7.5 years, ranging from 2 to 19 years. Of the group of patients in which flow cytometry revealed a normal DNA pattern, eight of 15 (53%) are still alive and in good health, with a mean survival period of 8 years. These results indicate that both techniques are reliable methods for obtaining prognostic information in Ewing's sarcomas. However, cytophotometry in situ yielded a better discrimination for the overall survival (P < 0.01) than did flow cytometry (P < 0.05). In 19% of the cases there was a discrepancy between the DNA histograms obtained with the two techniques. In five of 26 cases the DNA distributions were classified as normal by one method and aneuploid by the other. Tumour cell representation or selective loss of cells during enzymatic treatment may be responsible for this discrepancy.

Adolescent↗
PubMed1992

Occurrence and characterization of acyclovir-resistant herpes simplex virus isolates: report on a two-year sensitivity screening survey.

For the past 2 years, a survey network was established for the screening of acyclovir (ACV)-resistant clinical isolates of herpes simplex virus (HSV). Among 889 strains tested for in vitro ACV sensitivity, 14 HSV-1 and 6 HSV-2 were resistant to ACV concentrations exceeding 3 micrograms/ml. These resistant isolates were most often obtained after prolonged ACV treatment of severely immunocompromised patients. For five patients, the emergence of ACV-resistant virus correlated with treatment failure. In particular, a decrease in the in vitro sensitivity to ACV was observed for eight successive HSV-1 isolates from one immunodeficient patient undergoing therapy. All ACV-resistant isolates were studied for their sensitivity to different antiherpetic compounds and showed various cross-sensitive and -resistant patterns. The examination of viral populations by plaque autoradiography procedures frequently revealed their heterogeneity in terms of thymidine kinase (TK) phenotype and allowed the detection of various proportions of TK-positive (TK+), TK-deficient (TKD), or TK-altered (TKA) viruses. Our data underline the importance of monitoring the emergence of drug-resistant virus during the course of antiviral therapy, and the need for the detection and characterization of TK mutants in clinical specimens. The routine examination of drug sensitivity of HSV isolates provides useful information to clinicians for the management of ACV treatment in the hope of preventing ACV-resistant mutants from becoming predominant in mixed viral populations.

Acyclovir↗
PubMed1992

[Reversibility of IUdR resistance to sensitivity to an HSV1 strain in experimental keratitis in rabbits].

During 7 serial passages of Herpes Simplex Virus (HSV1) in rabbit cornea treated with idoxuridine (IUdR) (P1 to P7), the emergence of resistance had been obtained from P3. The reversion towards IUdR sensitivity has been investigated from either viral population P3 or P6 by 6 serial passages in rabbit cornea treated by Vaseline (V1 to V6). From viral population P3, the reversion to IUdR sensitivity has been obtained at V4. In contrast, from viral population P6, the IUdR resistance was conserved from V1 to V6. In vitro, on Vero cells, the effective doses 50% (ED50) and 90% (ED90), determined by dye uptake assay and plaque reduction assay, confirmed the reversibility towards IUdR sensitivity obtained from P3 and the stability of IUdR resistance from P6.

Animals↗
PubMed1991

Emergence of cross-resistant herpes simplex virus following topical drug therapy in rabbit keratitis.

The acquisition of drug resistance in vivo was investigated by 7 serial passages (from P0 to P7) of herpes simplex virus (HSV-1) in rabbit cornea treated with either IUdR (idoxuridine), IDC (idoxycytidine), ACV (acyclovir), TFT (trifluridine), or Ara A (adenine arabinoside). Therapeutic failure was acquired gradually: at P3 for IUdR, at P4 for ACV and at P5 for TFT. At P7, viral thymidine kinase (TK) activity was reduced to 5.6% of the parental strain for IUdR, to 7.5% for ACV and to 4.6% for TFT treatment. No signs of clinical unresponsiveness occurred with IDC or Ara A. The in vitro determination of antiviral drug sensitivity performed by the dye-uptake assay on HSV isolates at each passage showed a correlation between the increase in the 50% effective dose (ED50) and the increase of ulcer area grade at each passage under antiviral drug (p less than 0.1). Both IUdR- and TFT-resistant HSV1 developed cross-resistances to TK dependent drugs. However ACV-resistant HSV1 did not show cross-resistance to other antiviral TK dependent drugs. The acquisition of the cross-resistances is discussed, and the practical implications in case of therapeutic failures are suggested.

Animals↗
PubMed1987

HSV1 strain sensitivity in experimental rabbit keratitis: evolution under repeated topical IDU administrations.

The effects of repeated topical idoxuridine (IDU) administration of HSV1 strain sensitivity were investigated during 6 serial passages (P1 to P6) in the rabbit. By comparison to placebo treated rabbits, a delay in ulcer cicatrization appeared at P2 and clinical resistance was completed at P3. Clinical cross resistance to acyclovir (ACV) was also tested and demonstrated at P7. In vitro, a plaque reduction test on Vero cells using directly the tear film HSV populations allowed the prediction of the resistance by an early rise in the effective dose 90% (ED 90) value anticipating that in ED 50%. An ED 50 determination by dye-uptake assay on P6 HSV isolate demonstrated a cross resistance to viral thymidine kinase (TK) dependent drugs without any change in Ara-A and PFA sensitivity, according to a 23% TK activity at P6. At the last passage the HSV drug resistant population had an unrestricted corneal pathogenicity. A return to IDU and ACV in vitro sensitivity was demonstrated in group control animals at P2 but not at P4 or P6.

Acyclovir↗