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Biomedical subjects

C Ledent

Publications and source records attributed to C Ledent.

84 records · Page 5Linked to original sources
PubMed1991

Thyroid adenocarcinomas secondary to tissue-specific expression of simian virus-40 large T-antigen in transgenic mice.

A hybrid gene comprising the bovine thyroglobulin gene promoter and the coding region for the simian virus-40 large T- and small t-antigens was used to generate 30 transgenic mice by microinjection into the pronuclei of single cell embryos. All animals except three developed, as single primitive pathology, a dramatic enlargement of the thyroid gland. Compression of trachea and esophagus, accompanied by dyspnea, inspiratory stridor, and dysphagia, led to a progressive cachexia and premature death attributed to respiratory failure. Despite the large thyroid volume, T4 levels were abnormally low, and the progression of the syndrome could be delayed by a substitutive treatment with thyroid hormones. The rapid evolution of the disease, leading to the death of most founder transgenic animals before the breeding age, prevented transmission of the transgene to their offspring. Only two transgenic lines are presently surviving. Immunohistochemical analysis of the tissues revealed a specific expression of the simian virus-40 antigens in the thyroid cells. Hyperplasia was already obvious at birth. Older animals displayed moderately to poorly differentiated thyroid adenocarcinomas. Electron microscopy revealed, however, the persistence of cell polarity and the presence of microfollicles between the densely packed cells. Cell lines derived from these large T-expressing thyroids were shown to have lost expression of both thyroglobulin and thyroperoxidase, while expressing low levels of TSH receptors. These transgenic mice could constitute an interesting model of aggressive adenocarcinoma, sharing phenotypical similarities with the anaplastic type of human thyroid tumors.

Adenocarcinoma↗
PubMed1991

Specific ablation of thyroid follicle cells in adult transgenic mice.

The coding region of the herpes simplex type 1 virus thymidine kinase gene was coupled to the promoter of the bovine thyroglobulin gene and introduced into the genome of mice. The viral thymidine kinase (HSV1-TK) was expressed mainly in the thyroid glands and testis. Upon treatment of transgenic females with the antiherpetic agent Ganciclovir the thyroid regressed, while the parathyroid gland was unaffected. The number of thyroid follicle cells was greatly reduced after 3 days, and they were completely absent after 7 days of treatment. After 14 days, the levels of circulating T4 and T3 were below the limits of detection, total soluble protein recovered from the thyroid and parathyroid glands together was 10% of the control value, and the level of thyroid HSV1-TK was more than 100-fold lower than that in transgenic controls. Levels of circulating PTH and calcitonin remained normal. At the time of treatment the mice were adults. Thus, the thyroid follicle cells were selectively ablated after normal development with a functional thyroid gland. When treatment with Ganciclovir was terminated after 14 days, no circulating T4 or T3 or other indications of thyroid regeneration were detected for a subsequent period of 90 days. During this time the mice gained weight more slowly than controls, at a rate consistent with the suppression of GH synthesis by thyroid deficiency. The production of mouse major urinary protein (MUP) ceased in the treated mice and was completely restored by the administration of T4. MUP production was not restored by GH, demonstrating that the expression of the Mup genes requires T4 in addition to GH.

Animals↗
PubMed1991

The TSH cyclic AMP cascade in the control of thyroid cell proliferation: the story of a concept.

Thyrotropin stimulates the growth and proliferation of thyroid cells in vivo. Starting in the 1970, we have progressively shown that these effects could be reproduced in vitro in dog thyroid cells in primary culture. They are accompanied by the expression of differentiation. All the effects of thyrotropin are mediated by the cyclic AMP cascade. The best argument that this concept applies in vivo is the generation of hyperfunctioning adenoma involving the whole gland in transgenic mice expressing the constitutively active adenosine A2 receptor in the thyroid.

Animals↗
PubMed1991

Two years treatment with almitrine bismesylate in patients with hypoxic chronic obstructive airways disease.

Eighty nine patients with hypoxic chronic obstructive airways disease (COAD) were enrolled into the 1 year Vectarion International Multicentre Study-VIMS in 4 centres, Sheffield (UK), and Antwerp, Liege and Namur (Belgium). At the end of the year the remainder were invited to continue taking placebo or almitrine bismesylate (100-200 mg daily) in the same double blind manner for a further 12 months. In the almitrine treated patients mean arterial oxygen tension (Pao2) at the end of the treatment period improved from 7.5 (0.5) kPa to 8.2 (1.3) kPa (p less than 0.01) and arterial carbon dioxide tension (Paco2) fell from 6.1 (0.8) kPa to 5.8 (0.9) kPa (p less than 0.01). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and measurements of breathlessness were unchanged. In the placebo treated group changes in the above variables were not significant. Twenty nine patients withdrew from the almitrine group with seven deaths and six cases of peripheral neuropathy, and 22 patients withdrew from the placebo group with six deaths and two cases of peripheral neuropathy. Death rates between the groups were not significantly different. In conclusion, 2 yrs of almitrine treatment (100-200 mg daily) leads to a persistent slight improvement in PaO2 and PaCO2 but no benefit in survival was demonstrated. Patients in this study had a high incidence of drug related side-effects. Lower dose schedules should be investigated.

Almitrine↗
PubMed1990

Tissue-specific expression and methylation of a thyroglobulin-chloramphenicol acetyltransferase fusion gene in transgenic mice.

Fusion genes containing 1600 or 2000 base pairs of the bovine thyroglobulin gene 5' flanking region and the chloramphenicol acetyltransferase (CAT) coding sequence were constructed and used to generate transgenic mice. Altogether, 24 independent transgenic lines were obtained, and the expression of the transgene was assayed by measuring the CAT activity in different tissues. Depending on the transgenic lines, the fusion gene was either silent in all tissues or specifically expressed in the thyroid. The level of expression was found to be highly variable from one line to another and to be regulated by thyrotropin in a manner similar to the natural thyroglobulin gene. The methylation status of the integrated DNA was tested by digestion of DNA extracted from thyroid and other tissues with the isochizomers Msp I and Hpa II. It was found that one of the Hpa II sites was demethylated specifically in the thyroid.

Animals↗
PubMed1990

[Hyalinizing granuloma of the lung].

The authors report a case of a 44 year old patient with bilateral nodular lesions with a slow but progressive evolution and associated with a non-specific clinical picture. A thoracotomy enabled the diagnosis of a hyalinising granuloma of the lung to be made. Subsequently the appearance of a new lesion, and the risks of mediastinal extension suggested the use of corticotherapy and this rapidly led to a normalisation of the clinical and biological picture; as regards the radiology a partial regression of the nodular lesions was noted, and after 36 months of treatment there were no new lesions.

Adult↗
PubMed1989

Identification of a cAMP-responsive region in thyroglobulin gene promoter.

The DNA sequences involved in transcription control by a cAMP-dependent mechanism have been localized in the thyroglobulin gene promoter region by a functional assay. The proximal 5'-flanking sequences from the bovine thyroglobulin gene were linked to the bacterial chloramphenicol acetyl-transferase gene. Transient expression of this reporter gene was studied in dog thyrocytes in primary culture in the presence, or absence, of cAMP stimulation. Deletion analysis showed that the cAMP-responsive region is contained within the first 250 base-pairs of the promoter, and suggests that it could correspond to a sequence conserved between species. These DNA sequences do not bear significant homology with cAMP-responsive elements (CRE) described previously. By contrast, some similarities were found with the fat-specific element (FSE2) of genes under cAMP control in adipocytes and with DNA elements mediating cAMP-dependent regulation of expression of two different genes in the lower eukaryote Dictyostelium discoideum. This suggests that control of Tg gene transcription by cAMP could involve a mechanism different from the one mediated by a classical CRE.

Adipose Tissue↗
PubMed1980

Controlled trial of the effect of repeated administration of ipratropium bromide on ventilatory function of patients with severe chronic airways obstruction.

A trial was designed to assess whether repeated administration of ipratropium bromide for two weeks produced greater improvement than was obtained after a single dose. The effect of ipratropium bromide was compared with that of a placebo during a double-blind cross-over randomized trial in patients with advanced chronic airways disease in a stable state. Ipratropium bromide and placebo were both administered by metered dose inhaler for 14 days. There was a slight statistically significant improvement of conductance, thoracic gas volume, FEV1 and VC after inhalation of ipratropium bromide, but repeated doses of the drug did not produce progressive improvement.

Airway Obstruction↗