Biomedical subjects

Jean-Louis Kraimps

Publications and source records attributed to Jean-Louis Kraimps.

7 recordsLinked to original sources

PubMed2006

[GRKs and arrestins: the therapeutic pathway?].

Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of beta-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests.

Arrestins↗

PubMed2005

Pathophysiological roles of G-protein-coupled receptor kinases.

G-protein-coupled receptor kinases (GRKs) interact with the agonist-activated form of G-protein-coupled receptors (GPCRs) to effect receptor phosphorylation and to initiate profound impairment of receptor signalling, or desensitization. GPCRs form the largest family of cell surface receptors known and defects in GRK function have the potential consequence to affect GPCR-stimulated biological responses in many pathological situations. This review focuses on the physiological role of GRKs revealed by genetically modified animals but also develops the involvement of GRKs in human diseases as, Oguchi disease, heart failure, hypertension or rhumatoid arthritis. Furthermore, the regulation of GRK levels in opiate addiction, cancers, psychiatric diseases, cystic fibrosis and cardiac diseases is discussed. Both transgenic mice and human pathologies have demonstrated the importance of GRKs in the signalling pathways of rhodopsin, beta-adrenergic and dopamine-1 receptors. The modulation of GRK activity in animal models of cardiac diseases can be effective to restore cardiac function in heart failure and opens a novel therapeutic strategy in diseases with GPCR dysregulation.

Animals↗

PubMed2005

Management and prognosis of metastases to the thyroid gland.

BACKGROUND: Intrathyroid metastases (ITM) of extrathyroid cancer are rare and have a poor prognosis. The aim of this work was to identify the sites of primary cancers and the treatment and prognosis of these lesions. STUDY DESIGN: This retrospective study was carried out on patients treated between 1982 and 2002 in the surgical departments of the University hospitals of Poitiers, Limoges, Tours, and Nantes, France. All diagnoses were confirmed by cytology or histologic examination. RESULTS: Twenty-nine patients (41 to 78 years) had ITM. Primary cancers were renal cell in 16 patients, lung in 4, digestive in 4, sarcoma in 1, melanoma in 1, neuroendocrine in 1, and of unknown origin in 1 patient. For 10 patients, diagnoses of primary cancer and ITM were synchronous. For 19 patients, delay between diagnosis of the primary cancer and ITM was 6.8 years (2 months to 16 years). Diagnosis was confirmed with fine-needle aspiration 3 times and with histologic examination of the thyroid 26 times. Twenty-seven patients had thyroidectomy; two were not operated on. After treatment of ITM, 13 patients had new metastatic sites. Mean followup for all patients was 2.3 years. Seven patients (24%) (6 with renal cancer) were disease free (followup 4.5 years). Four patients were alive with disease (followup 1.4 years). Eighteen patients (62%) died of their disease at a mean delay of 1.4 years. CONCLUSIONS: ITM are rare but the diagnosis should be borne in mind when patients have a history of cancer (mainly renal cancer). Preoperative diagnosis and complete evaluation could avoid unnecessary thyroidectomy because numerous patients had diffuse metastases.

Adult↗

PubMed2005

Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature.

Cushing's syndrome (CS) in medullary thyroid carcinoma (MTC) is rare. Only 50 cases have been reported. We report 10 cases of MTC with ectopic adrenocorticotropic hormone (ACTH)-dependent syndrome (EAS), analyzed retrospectively. Among 1640 patients with MTC, 13 developed EAS (0.7%). In 10 patients CS could unequivoqually be related to MTC (0.6%). CS was always clinically obvious. It revealed MTC in 3 cases and followed diagnosis by an average of 34.5 months in the others. Metastases were often present at diagnosis. Immunohistochemistry with ACTH antibodies was positive in one case. Diagnosis of ectopic CS was established according to clinical and biologic features, and absence of corticotropic adenoma as well as parallel evolution between tumor and CS. Therapy was medical and surgical: anticortisolic drugs alone or in association with somatostatin analogue, somatostatin analogue alone, and bilateral adrenalectomy. Eight patients died within 2 to 30 months, 4 of hypercortisolism complications (3 peritonitis and 1 hypokalaemia), 4 of MTC progression. EAS is a rare complication of MTC. The prognosis is poor because of frequency of metastasis at diagnosis. Persistent hypercortisolism can, by itself, lead to death, and has to be treated specifically.

Adrenocorticotropic Hormone↗

PubMed2004

Risk factors for recurrent nodular goiter after thyroidectomy for benign disease: case-control study of 244 patients.

Surgery for recurrent nodular goiter is associated with a significant risk of parathyroid and recurrent laryngeal nerve (RLN) morbidity. Total thyroidectomy for benign disease is assessed. The aim of this study was to evaluate the risk factors for recurrence and the morbidity associated with reoperation. From 1969 to 1996 a total of 4334 thyroidectomies were performed, of which 122 were for recurrent nodular goiter (group I: 116 women, 6 men). A matched case-control study of 122 patients operated on for nonrecurrent multinodular goiter was performed (group II: 112 women, 10 men). Age, family history, initial surgery, pathology, and morbidity were compared in the two groups by chi2 test, Fisher's exact test, and the Mantel-Haenszel test. The mean age was 39.88 years in group I and 47.89 years in group II. There was no statistical difference in relation to the extent of thyroidectomy or morbidity after initial surgery. Statistical differences were identified regarding age (p = 0.000002) and the multinodular nature of the initial goiter (p = 0.005). Bilaterality and family history were less significant (p = 0.09 andp = 0.08, respectively). Temporary RLN palsy and temporary hypoparathyroidism were higher in group I (12.3% vs. 5.7%,p = 0.0737; 10.6% vs. 1.7%, p = 0.00337). Permanent RLN palsy was found in 0.8% in group I and in none in group II (p = 0.5, NS). Young age and multiple nodules at initial surgery are risk factors for recurrence. A higher rate of temporary morbidity was demonstrated after surgery for recurrent goiter. Total thyroidectomy for multinodular goiter is advisable.

Adolescent↗

PubMed2002

Expression and activity of g protein-coupled receptor kinases in differentiated thyroid carcinoma.

Most of the TSH effects on the proliferation and differentiation of thyroid cells are mediated by cAMP via an adenylyl cyclase-activating Gs protein. TSH receptor responsiveness in cell cultures, is regulated by G protein-coupled receptor kinase (GRK) 2 and 5. To determine whether an alteration in activity and expression of GRKs might be associated with variable levels of TSH receptor desensitization in vivo, we studied human thyroid tissues including 21 normal tissues and 18 differentiated carcinomas. GRK activity was assayed by rhodopsin phosphorylation, and GRK protein and mRNA expressions assessed by immunoblotting and real-time quantitative RT-PCR, respectively. GRK2 and GRK5 were found as the predominant isoforms in the human thyroid. GRK5 protein expression was significantly decreased in differentiated thyroid carcinoma (P < 0.02) and paralleled a decrease in GRK mRNA expression (P < 0.02). In contrast, no difference in protein and mRNA levels of GRK2 were observed between normal and cancerous thyroid tissues. Although GRK2 protein levels correlated with GRK activities, we demonstrated a significant increase in GRK activity in differentiated thyroid carcinoma (P < 0.02). Less TSH receptor desensitization occurred in differentiated carcinoma than in normal thyroid tissue, as judged by TSH-stimulated cAMP response in human thyroid cells in primary culture. In conclusion, this study indicates that GRK2 activity and GRK5 expression have opposite regulations in cancer cells. Furthermore, the decrease in GRK5 expression may underlie the reduction in homologous desensitization of the TSH receptor in differentiated thyroid carcinoma, contributing to explain the increased cAMP levels in these tumors.

Adenocarcinoma, Follicular↗

PubMed2002

[Update on differenciated thyroid carcinoma].

Differenciated thyroid carcinomas are the most frequently encountered endocrine tumours. These hormono-dependent carcinomas have a good prognosis. Data derived from molecular biology allowed a better understanding of pathophysiological mechanisms involved in tumorigenesis of thyroid papillar and follicular carcinomas. The use of the works derived from molecular biology also allowed a better diagnostic and therapeutic management of the thyroid cancer patients, particularly using recombinant human TSH. Familial thyroid cancer disease must also be recognised to optimise the clinical managemet of patients and their family.

Adenocarcinoma, Follicular↗