Biomedical subjects
Publications and source records attributed to G Lefranc.
Ultrathin sections are stained immediately after cutting by placing them in contact with staining solution and then placed on a slide covered by a celloidin film. This method largely avoids precipitates of heavy metals. The recovering of celloidin film is improved using a stainless steel basket. This technique is far more reliable than that involving use of a filter paper.
Previously we reported a gross genetic polymorphism of the human immunoglobulin heavy chain locus manifest by a large internal deletion within the constant region gene segment. We now describe a detailed serological and molecular genetic study of a Tunisian family in which members appear to carry two chromosomes 14 with different DNA deletions. The first is similar to that previously described encompassing three gamma subclass genes, a pseudo-epsilon gene and the alpha 1 subclass gene; the second deletion is less complex involving only the pseudo-epsilon gene and the alpha 1 gene.
The existence of specific probes for human genes makes it feasible to study genetic abnormalities, both inherited and acquired, at the level of the genome. In this respect, the antibody genes of man are of particular interest as they represent a multigene family expressed in many leukaemias and immunodeficiency diseases. Furthermore, selective deficiency of immunoglobulins has been described in healthy individuals. Normally, human adults express five types of immunoglobulin--IgM, IgD, IgG, IgE and IgA (defined by the class of heavy chain constant region). Subclasses are also known in IgG (IgG1, IgG2, IgG3 and IgG4) and IgA (IgA1 and IgA2) in which the immunoglobulins contain gamma 1, gamma 2, gamma 3 or gamma 4 and alpha 1 or alpha 2 CH regions, respectively. Recently, a healthy Tunisian person was described who showed abnormal patterns of immunoglobulin expression. The serum immunoglobulin of this individual, designated TAK3, was confined to IgM, IgD, IgG3, IgE and IgA2. We have now used cloned CH-gene probes to study the DNA of TAK3 as well as two brothers, also Tunisian but apparently unrelated to the individual TAK3, and who show a similar immunoglobulin abnormality. We found that in these cases there seems to have been a large chromosomal deletion which includes three gamma genes, an alpha gene and a pseudo-epsilon gene. This deletion accounts for the simultaneous absence of certain H-chain subclasses. These results illustrate that the human immunoglobulin gene locus is capable of undergoing rapid change, which is particularly apparent within small populations in which consanguinity is common.
A high-resolution autoradiographic study was conducted on 268 thin sections of endocrine cells in the rabbit colon following injection of (3H) L-dopa. Using quantitative autoradiography, silver-proteinate impregnation, granulometry, and statistical analysis of cell populations by the Falck procedure, three cell types were identified--EC, L; and H--as well as a single cell with distinct ultrastructural characteristics. For the first time, a fine quantitative estimation of the handling ability of amine precursor related to the cross-sectional areas of each cell type was obtained, using a Kontron Digiplan image analyzer. All cells studied showed the ability to take up the precursor. Labeling indices were 6.63, 2.15, and 2.14 for EC, L, and H, respectively. These data and silver-proteinate impregnations provide good criteria for differentiating EC from H cells despite morphological similarities. After critical analysis of granule diameters, L cells were considered to be pluripotential in secretory activity.
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Inheritance of an excess of immunoglobulin allotypes in one haplotype was encountered which could not be explained by the assumption of a duplicated locus. The surplus of allotypes was related to markers on the CH3 domain of gamma 3 chains. Two such cases were investigated extensively. The IgG3 molecules were isolated by gel filtration and by absorption on protein A. Only the usual combination of allotypes appeared to be present on the IgG3 molecules. The supernumerary markers were found in one case on IgG2 molecules and in the other case on IgG1 molecules. This followed from investigations of eluates after separation of the subclasses by immune absorptions. A hypothesis was proposed to explain these events by mutation of a particular position of an otherwise homologous stretch of gamma-subclass DNA.
Unusual combinations--unexpected sets, excess of lack--of antigenic determinants, or Gm allotypes, on the constant regions of the heavy chains of the human IgG1 and IgG3 immunoglobulins are accounted for in terms of genetic events (exchanges, duplications and deletions) involving the DNA sequences, or exons, coding for the three CH1-, CH2- and CH3 domains of the gamma 1 and gamma 3 chains. Equal and unequal cross-overs at the level of the introns without damage to the CH exons are postulated.
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About a retrospective study turning on 600 bed-rests during 3 years, the writers study 433 confirmed high blood pressures including 389 without therapeutic among which 67 p. 100 labil or limit H.B.P. and 33 p. 100 permanent H.B.P. By light of current ideas and withdrawn informations from complementary explorations done, they try to define a reasonable attitude concerning twenty years old young hypertensive male patients in view of selection. This attitude can be extended to the general field of young H.B.P. people. They establish that a good number of systemically researched elements are without great interest; functional signs, which are more the neurotonia witness than the H.B.P. consequence, heart or renal repercussion, negligible in this age, the too shematic distinction between permanent, labil or limit H.B.P. On the other hand, some parameters deserve to be searched : family antecedents (greater than 60 p. 100), obesity (approximately 20 p. 100), ocular repercussion (approximately 15 p. 100), perturbation of lipidemia, above all hypertriglyceridemia, hyperuricemia and urinary sediment abnomalies. As for I.V.U., in spite of an exact study of vascular times, and second reading by the same observer, it never allowed to display any renovascular H.B.P. Other pathologic uronephrologic established images are all almost associated to urinary sediment anomalies or to proteinuria. More, a few frequent incidents among young people and the price of the exam bring to purpose. I.V.U. only when H.B.P. context is hard or going with urinary signs. Other more specific exams (V.M.A., catecholamines) will be asked according to the context.
Simultaneous subtyping of two genetic markers--group-specific component (Gc) and transferrin (Tf)--by electrofocusing enabled us to compute the following gene frequencies for the Tunisian population: Gc1S, 0.525; Gc1F, 0.260; Gc2, 0.215; TfC1, 0.770; TfC2, 0.215; TfD1, 0.015. The frequencies of TfD, TfC2, and Gc1 are higher than those found in Caucasoid populations and can be explained by Negroid contribution. A selective advantage related to the metabolic role of this vitamin D-binding protein does not seem very likely for any particular Gc type or subtype. It is postulated that the differences in the frequencies of the Gc alleles might be related to selective advantage for genes belonging to other genetic systems originally closely linked to either Gc1 or to Gc2 alleles.
Cord blood samples, collected at Sousse and Monastir, from Tunisian newborns were focused on a thin layer of agarose in order to detect the carriers of the A gamma 75Thr chain (A gamma chain bearing a replacement Ile-->Thr at position 75). Nineteen individuals (10%) were positive for this variant. The frequency of the A gamma 75Thr gene in the Tunisian population (0.050) is compared with that of various ethnic populations.
Hypohaptoglobinaemia and ahaptoglobinaemia occurred in three generations, mainly to male members of a family. Also small amounts of haptoglobin were detected in most of the female relatives. Haemolytic anaemia seemed likely and the glucose 6 phosphate dehydrogenase (G.6.P.D.) activity was normal. The probable genotype of these apparently healthy individuals was Hp2/Hp2. These preliminary data might suggest a defect in control of gene expression by steroid hormones.
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Constant, intense and precise impregnation of enterochromaffin (EC) cells was achieved simply by floating thin or semithin sections of gut mucosa, fixed in osmium tetroxide or in glutaraldehyde with postfixation in osmium, on a silver nitrate or proteinate solution. EC cells alone showed impregnation in the light microscope. In the electron microscope, impregnation affected not only the secretory granules of EC cells but also, although much more faintly, those of other, non-EC cells (D, X, D1, G and other cells). Lysosomes also showed partial or total reactivity. Oxidation reduced but did not entirely suppress EC cell staining and had no effect on non-EC endocrine cell staining. Since the reaction did not occur with glutaraldehyde alone, osmium appeared to be a crucial component of the process. These findings should be borne in mind in applying Thiery's method for vicinal glycol groups to the type of study material used in these experiments.
The thiocarbohydrazide-silver proteinate (TCH SP) method was applied to the study of cat, rabbit and mouse gastric mucosa endocrine cells. After 24-h treatment with thiocarbohydrazide (TCH), glycogen was seen in the hyaloplasm of X, D, P, A and O cells but not in EC, EC-like or D1 cells. With flotation times as short as 30 to 40 min glycogen was readily detected in X cells. Secretory granules of EC cells were constantly stained, while those of D1 cells failed to react. In most experiments granules of X, A and O cells showed peripheral "staining", while in others staining of variable intensity affected the entire granular cross-section in X, D and P cells. With 72-h exposure to TCH, EC and EC-like cells showed particles resembling glycogen, even staining or only peripheral staining of certain EC cell granules. From the results of this and previous studies, EC cell staining is believed to be due wholly or partly, according to exposure times, to the action of silver proteinate, while that of certain non-EC cells is probably a specific indicator of complexed carbohydrates.
A study of Gm allotypes in a Caucasoid family with hypogammaglobulinaemic probands, showed qualitative (unexpected or lacking Gm allotypes) and quantitative (increased or decreased Gm contents) abnormalities in many relatives. Part of these observations can be most probably accounted for by inheritance of a GM1,17; 5,28 haplotype, not described in Caucasians yet, and by an in vivo expression of latent Gm genes.
Individuals with selective absence of IgG1 and IgG2 were discovered by testing for allotypes and isotypes of the respective sub-classes. These individuals were homozygous for sub-class deleted Gm-Am haplotypes, as shown by allotype studies in two families (Gm--;..;g;A2m1/Gm--;n;b;A2m1 and Gm--;n;b;A2m1/Gm--;..;b;A2m1) and by a population study of New Guineans (Gm fa;--;b;A2m2). The individuals with IgG1 sub-class deficiency showed elevation of IgG2, IgG4 and in particular of IgG3. Gene deletion can result from unequal crossing over which renders a complementary chromosome with a duplication of a sub-class gene. In one family, duplication of gamma 3 genes was observed to have happened in one of a twin pair. Quanitation of sub-classes in families with gamma 1- and with gamma 3-duplicated haplotypes did not show increased levels of the gene involved.