Biomedical subjects

O Chabre

Publications and source records attributed to O Chabre.

30 records · Page 2Linked to original sources

PubMed1998

[Early therapeutic management of patients genetically predisposed to medullary thyroid cancer].

STUDY: The aim of our study was to study therapeutic results after thyroidectomy in patients positive for predictive genetic analysis and with preoperative calcitonin (CT) response to pentagastlin (Pg) < 150 pg/ml. MATERIAL AND METHODS: 36 patients (13 F, 23 M) were selected: 13 F-MTC from 8 families, 22 MEN 2A from 15 families and 1 MEN 2B. They were positive for direct RET mutation analysis. CT was assayed by immunoradiometric method before and after Pg. Pg test results before and after thyroidectomy, age at operation and histologic results were analysed. RESULTS: Mean preoperative peak CT was 82.5 +/- 34.0 pg/ml (22-133): among these 36 patients preoperative basal and peak CT were normal in 16 and 2 patients respectively. F-MTC and MEN 2A patients were different according to their preoperative peak CT levels (58.1 +/- 24.0 vs 97.6 +/- 31.3) pg/ml, p < 0.01) and age at thyroidectomy (20.4 +/- 10.5 vs 11.6 +/- 7.6 years, p < 0.01 by Mann-Whitney test). Total thyroidectomy was performed in all patients at a mean age of 14.8 +/- 9.8 years (2.5-41.7) and was associated with lymph node dissection in 30 cases. The 2 F-MTC patients with normal preoperative peak CT levels had bilateral C-cell hyperplasia (CCH) associated with uni or bilateral micro-MTC. Other patients had uni or bilateral micro MTC except 4 who had isolated CCH without carcinoma. The age of two MEN-2A and 1 MEN 2B patients with micro-MTC ranged from 2.5 to 4.7 yr. Micro MTC was present in 100% of MEN-2A cases after the age of 10 yr. There were no lymph nodes metastases. During postoperative survey, the last PG tests (n = 33) were performed 27.5 months (1-92) after thyroidectomy: peak CT values were always < 10 pg/ml. IN CONCLUSION: Thyroidectomy should be performed at a very young age in RET mutation carriers, regardless of the plasma CT values. This choice is justified in NEM-2A and NEM-2B patients but must be discussed in F-MTC families with less aggressive forms of the disease.

Adolescent↗

PubMed1995

Hormonal regulation of mitogen-activated protein kinase activity in bovine adrenocortical cells: cross-talk between phosphoinositides, adenosine 3',5'-monophosphate, and tyrosine kinase receptor pathways.

Angiotensin-II (AII), which stimulates steroidogenesis in bovine adrenocortical (BAC) cells through the phosphoinositides pathway, activates p42-p44 mitogen-activated protein kinases (MAPKs) after 5 min of treatment (EC50 = 0.1 nM). This activation is 1) completely inhibited by the AII receptor AT1 subtype antagonist Dup 753 (10 microM), but unaffected by the AT2 antagonist PD 123177; 2) not reproduced by the AT2 agonist CGP 42112A; 3) insensitive to pretreatment with pertussis toxin; and 4) abolished by a 48-h preexposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 1 microM), which down-regulates protein kinase-C activity. Fibroblast growth factor-2, a potent mitogen for BAC cells, which acts through its tyrosine kinase receptor, also activates MAPK (EC50 = 0.3 in a TPA-insensitive manner, while exhibiting no detectable effect on BAC cell steroidogenesis. In contrast, ACTH, which stimulates steroidogenesis via cAMP and inhibits BAC cell proliferation, does not stimulate MAPK. Indeed, ACTH completely blocks (IC50 = 0.01 nM) the stimulation of MAPK by AII, fibroblast growth factor-2, or TPA. Therefore, bovine adrenocortical cells provide an example of positive and negative hormonal regulation of MAPK activity through a cross-talk between the inositide-, cAMP-, and growth factor-activated tyrosine kinase pathways.

Adenosine Monophosphate↗

PubMed1995

[Role of hormonal exploration in avoiding of the failures of anterior pituitary gland surgery in Cushing disease].

Patients with Cushing's disease are not cured by transsphenoidal microsurgery in about 30% of the cases. Beside the problem of invasive macroadenomas, these failures are due either to diagnostic errors, or to very small microadenomas that could no be found. Positive diagnosis of hypercortisolism is quite straightforward and the problem is sensitivity rather than specificity. Primary adrenocortical hypercortisolism should not be mistaken. Depression-related hypercortisolism can be difficult to distinguish from Cushing disease: most cases are recognized after clinical story and CRF stimulation test. Ectopic ACTH secretion by a carcinoid tumor represents at least 8% of ACTH-dependant hypercortisolism. It cannot be reliably distinguished from corticotroph microadenoma by either classical dynamic tests or anterior pituitary imaging. However measurements of ACTH in the inferior petrosal sinus under basal condition and CRF stimulation allow the diagnosis of central or peripheral ACTH secretion with a quasi 100% sensitivity and specificity. In contrast this technique is of poor help for the diagnosis of lateralization of corticotroph microadenomas, for which it gives erroneous results in 25 to 50% of the cases. Rapid intraoperative measurement of ACTH in peripituitary blood seems a more reliable approach. In our series it gave correct results in 11 out of 12 cases. In 1995 hormonal exploration of Cushing disease should limit the failures of anterior pituitary surgery to the cases of invasive macroadenomas that cannot be completely removed.

Adrenocorticotropic Hormone↗

PubMed1994

[G-proteins and endocrine tumors. The example of acromegaly].

Mutations of Gs are found in 30 to 40% of the pituitary tumours responsible for acromegaly (somatotrope tumor), 10% of secreting thyroid tumors, and in the rare McCune-Albright syndrome. Gs is a member of the G protein family, which plays a major role in the mechanism of action of many hormones by coupling their membrane receptors to molecules called effectors, which general intracellular second messengers. Gs is responsible for the coupling of many receptors to adenylate cyclase which synthetizes cyclic AMP. The effect of the mutations of Gs is to permanently activate adenylate cyclase by a mechanism similar to the one exerted by cholera toxin. In the somatotrope cells adenylate cyclase is normally under the control of the hypothalamic hormone GH-RH, which stimulates both growth hormone secretion and cell proliferation. The mutations of Gs allow the somatotrope to escape from the control by GH-RH and to secrete and proliferate in an autonomous way, which leads to the development of a tumor responsible for acromegaly. The same mechanism explains the presence of Gs mutations in the other types of endocrine tumors. Therefore, the mutations transform the gene of Gs into an oncogene, gsp, which represents the first molecular explanation of an old concept familiar to endocrinologists: the autonomy of the secretion and proliferation of endocrine tumors.

Acromegaly↗

PubMed1994

Coupling of the alpha 2A-adrenergic receptor to multiple G-proteins. A simple approach for estimating receptor-G-protein coupling efficiency in a transient expression system.

It is now widely appreciated that G-protein-coupled cell-surface receptors can modulate distinct signal transduction pathways via coupling to different GTP-binding proteins. In the present study, we have used a transient co-expression approach to study the coupling of a single alpha 2-adrenergic receptor (alpha 2AAR) population to three different G protein subtypes (Gi, Gq, and Gs) acting on two different cellular effectors in HEK 293 cells. In all cases, the affinity of the receptor for the alpha 2A-adrenergic agonist, UK14304, is unchanged (KD approximately equal to 670 nM). However, there is a dramatic difference in the EC50 of UK14304 in eliciting inhibition of endogenous adenylyl cyclase via endogenous Gi (0.09 nM) versus activation of phospholipase C via co-transfected Gq (50 nM) or stimulation of endogenous adenylyl cyclase via co-transfected Gs (70 nM) in HEK 293 cells. These findings are consistent with the interpretations that the alpha 2AAR preferentially interacts with Gi rather than Gs or Gq. When the alpha 2AAR was mutated at Asp79, a residue highly conserved among G-protein-coupled receptors, the mutant D79N alpha 2AAR lost the ability to couple to Gq and Gs and, although it was able to couple to inhibition of cyclase via pertussis toxin-sensitive pathways (Gi), it did so with a lower potency than observed for the wild-type alpha 2AAR (EC50 = 7.2 nM). The most straightforward interpretation of these data is that the D79N mutation in the alpha 2AAR reduces the efficiency of coupling of the alpha 2AAR to all G-proteins, thus eliminating signal transduction through those pathways less efficiently coupled to the alpha 2AAR. Since the transient expression assays described permit manipulation of the structure of both the receptor or the G-protein, the present strategies could be exploited to delineate the complementary domains specifying the affinity and/or efficacy of receptor coupling to distinct GTP-binding proteins.

Adenylyl Cyclase Inhibitors↗

PubMed1993

Oxygen availability as a regulatory factor of androgen synthesis by adrenocortical cells.

Molecular oxygen is an obligatory substrate of all cytochrome P-450 (cyt P-450) hydroxylases involved in the steroid biosynthetic pathways. However, oxygen-derived free radicals are highly destructive species resulting from cyt P-450-catalyzed steroid hydroxylation reactions. Cells in culture are usually exposed to an atmospheric pO2 that is well above the estimated in situ pO2 in vivo. It has been suggested that lowering pO2 might prevent the loss of biosynthetic enzymatic activities in bovine adrenocortical or Leydig cells in culture. The present study was performed to examine the effect of low pO2 pressure (1% oxygen in the gas phase) compared to routinely employed conditions (19% oxygen) on bovine adrenocortical cell steroidogenic activities under both basal and stimulated conditions. Lowering the pO2 showed no significant effect on the cultured adrenocortical cell proliferation rate or their ability to produce cortisol. By contrast, it resulted in a dramatic drop in androgen secretion and a slight increase in corticosterone synthesis. The mechanism involved in the qualitative modulation of steroid biosynthesis by oxygen availability was examined in some detail using purified steroid hydroxylase components. We found that cyt P-450(17 alpha, which can catalyze both the steroid 17 alpha-hydroxylation and the 17-20-lyase reaction is probably the major target explaining the oxygen effect. Indeed, cyt P-450(17 alpha) hydroxylase activity exhibits a clearly higher affinity for oxygen (Km, 22 microM) than its lyase activity (Km, 66 microM). These observations suggest that 1) oxygen availability is able to modulate the balance between androgen and corticosteroid pathways in bovine adrenocortical cell; and 2) adrenocortical cell functions studied in vitro under relatively high pO2 do not exactly reflect the in vivo situation.

Adrenal Cortex↗

PubMed1992

[Cutaneous lesion associated with multiple endocrine neoplasms type 2A (Sipple's syndrome). An early clinical marker].

We report the association of a cutaneous lesion with multiple endocrine neoplasia type 2A (MEN 2A) in three patients from a French family. These lesions are very similar to those previously described in an Italian and an American MEN 2A family and called cutaneous lichen amyloidosis. In all three families the patients presented with a pruritic and pigmented cutaneous lesion localized unilaterally on the upper back. However, in the French family the patients also complained of paroxysmal pain in the same area, in which we could elicit a touch hypoesthesia and pain hyperesthesia. Such an association of cutaneous and neurological features in the upper back is known as Notalgia Paresthetica (NP). NP is believed to represent a neuropathy of the posterior dorsal nerve rami. Unlike the two previously reported families, the histological, immunohistochemical and ultrastructural analysis of the skin biopsies of the French patients did not show any amyloid material. This suggests that the presence of amyloid may not be a constant feature of the cutaneous lesions associated with MEN 2A. We consider these lesions as a form of dorsal neuropathy rather than a cutaneous lichen amyloidosis. Whatever their origin, these cutaneous lesion usually precede the appearance of the neoplastic lesions of MEN 2A. They may act as an early clinical marker that must be searched for in each subject at risk for MEN 2A. In addition, all patients presenting with NP should be screened for MEN 2A.

Adrenal Gland Neoplasms↗

PubMed1992

Recombinant Gq alpha. Mutational activation and coupling to receptors and phospholipase C.

Gq mediates hormonal stimulation of phosphoinositide-specific phospholipase C (PI-PLC). We mutated the alpha subunit of Gq (alpha q) to replace arginine 183 with cysteine. Mutations that substitute cysteine for the corresponding arginine residues of alpha s and alpha i2 constitutively activate their respective effector pathways, creating the gsp and gip2 oncogenes. Transient expression of alpha q-R183C in COS-7 and HEK-293 cells constitutively activates PI-PLC, but wild type (WT) alpha q does not. This suggests that the mutated arginines in alpha s, alpha i2, and alpha q share a common function in regulating the active state of these proteins and that the alpha q gene may serve as a target for oncogenic mutations in human tumors. In an attempt to develop an assay for receptor stimulation of recombinant alpha q, we co-expressed receptors with alpha q-WT. We found that the alpha 2-adrenoceptor stimulates PI-PLC activation in HEK-293 cells in a fashion that depends completely on co-expression of alpha q-WT. These findings create an experimental model, similar to that provided for alpha s by S49 cyc- cells, that should make it possible to analyze receptor and effector coupling by mutant alpha q against a null background.

Adenylyl Cyclase Inhibitors↗

PubMed1992

A recombinant calcitonin receptor independently stimulates 3',5'-cyclic adenosine monophosphate and Ca2+/inositol phosphate signaling pathways.

Calcitonin (CT), a polypeptide hormone, regulates calcium homeostasis by activating surface receptors coupled to stimulation of adenylyl cyclase in bone and kidney cells. CT has also been reported to increase cytoplasmic Ca2+ in osteoclasts and renal tubule cells. Signaling pathways activated by a recombinant porcine renal calcitonin receptor transiently expressed in HEK-293 cells were studied. In cells expressing the recombinant CT receptor, salmon CT stimulated cAMP accumulation (EC50, 0.16 nM) and synthesis of inositol phosphates (IP; EC50, 3.7 nM). Two other recombinant receptors, the m1-muscarinic acetylcholine receptor and the LH receptor, activated synthesis of either IP or cAMP, respectively, but not both. Stable expression of the CT receptor in a CT receptor-deficient cell line, M18, restored the cells' ability to increase cytoplasmic Ca2+ in response to salmon CT. These results show that a single recombinant CT receptor can independently activate effector pathways mediated by cAMP and IP/Ca2+.

Animals↗

PubMed1992

[Catheterization of the inferior petrosal sinus. Its role in the diagnosis of Cushing's syndrome. Experience with 23 explorations].

Selective catheterization of the inferior petrosal sinus has been performed in 23 patients: 11 Cushing's disease, 5 lung carcinoid tumors whose diagnosis has been confirmed by surgery and 7 ACTH-dependent hypercortisolism whose final diagnosis has not yet been proved. The pituitary origin of hormone secretion is accepted if the central-to-peripheral ratio (C/PR) is equal or greater than 2 on basal values and/or during CRF test. On basal values, all subjects but one with confirmed pituitary lesions exhibited a C/PR > or = 2; the carcinoid tumors never exceeded the value of 1.3. After CRF injection, all the pituitary tumors showed an increase in C/PR; one patient with a lung carcinoid tumor (CRF-negative) showed a pituitary ACTH secretion (C/PR = 3.7). The localization of pituitary adenoma by the lateralization of hormone secretion is disappointing, except, perhaps, for very small extremely lateral adenomas. No accident occurred in our series, nor in the literature. This investigation seems the most reliable approach to prove the pituitary origin of hormonal hypersecretion. We recommend it to be performed in ACTH-dependent Cushing's syndrome when the secretory pattern is not typical and/or pituitary imaging is normal.

Adenoma↗

PubMed1992

Cutaneous lesion associated with multiple endocrine neoplasia type 2A: lichen amyloidosis or notalgia paresthetica?

Three patients of a French family demonstrated an association of multiple endocrine neoplasia type 2A (MEN 2A) with a pruritic scapular skin lesion. The lesions are similar to those described as familial cutaneous lichen amyloidosis in unrelated MEN 2A and medullary thyroid carcinoma families, but histological, immunohistochemical, and ultrastructural analysis of skin biopsies from each patient in the French family did not show amyloid deposition. The topography of the lesion follows dermatomes C8-D3. The patients report not only pruritus but also paresthesia and hyperalgesia, and one showed touch hypoesthesia and pain hyperesthesia in the area of the lesion. Such an association of cutaneous and neurological features suggests notalgia paresthetica (NP), a neuropathy of the posterior dorsal rami nerves. We thus suggest that the cutaneous lesions associated with MEN 2A might be secondary to pathology in the neural crest-derived dorsal sensory nerves. The amyloid, when present, would be secondary to scratching. We propose that patients presenting with familial NP be suspect for MEN 2A.

Adult↗

PubMedDate not supplied

Gastric inhibitory polypeptide (GIP) stimulates cortisol secretion, cAMP production and DNA synthesis in an adrenal adenoma responsible for food-dependent Cushing's syndrome.

We studied in vitro an adrenal tumor responsible for food-dependent, ACTH independent, Cushing's's syndrome. Cortisol secretion by isolated tumor cells was stimulated by GIP and ACTH, but not by the gut hormone glucagon-like peptide-1 (GLP-1). Both GIP and ACTH stimulated production of cAMP but not inositol 1,4,5-trisphosphate IP3). In quiescent tumor cells, GIP and ACTH stimulated [3H]-thymidine incorporation and p42-p44 MAP kinase activity. In normal human adrenocortical cells cortisol secretion and [3H]-thymidine incorporation were stimulated by ACTH but not by GIP. GIP receptor mRNA, assessed by RT-PCR, was highly expressed in the tumor, but undetectable in the adjacent hypotrophic adrenal tissue, in a normal adrenal, in two adrenal tumors responsible for food-independent Cushing's syndrome and in two hyperplastic adrenals associated with ACTH hypersecretion. Low levels of ACTH receptor mRNA were also detectable in the tumor. We conclude that abnormal expression of the GIP receptor allows adrenocortical cells to respond to food intake with an increase of cAMP that may participate in stimulation of both cortisol secretion and proliferation of the tumor cells.

Adenoma↗