Eric Laurent

Dual activation by thyrotropin of the phospholipase C and cyclic AMP cascades in human thyroid

In human thyroid slices prelabeled with myo-[2-3H]inositol, thyrotropin (TSH, 3-30 mU/ml) stimulated IP3, IP2 and IP1 generation over a prolonged time course. The cAMP response was much more sensitive to TSH, peaking between 1 and 5 mU/ml. Forskolin (10(-5) M) and isoproterenol had no effect on basal IP levels, while carbamylcholine (10(-5) M, 10(-4) M) also increased IP accumulation. These data suggest that in the human thyroid, TSH activates a phospholipase C generating IP3 and diacylglycerol independently of the well-known adenylate cyclase stimulation. They validate in the human model a dual mode of action of the hormone previously proposed on the basis of indirect observations.

ATP, bradykinin, TRH and TSH activate the Ca2+-phosphatidylinositol cascade of human thyrocytes in primary culture

We have recently shown that adenosine triphosphate (ATP), bradykinin and thyrotropin-releasing hormone (THR) increase the ([Ca2+]i) of human thyrocytes in primary culture. We show here that these agents also stimulate the generation of [3H]-inositol monophosphate (IP1), inositol bisphosphate (IP2) and inositol trisphosphate (IP3). The stimulation of IP3 generation followed two distinct kinetics: it was sustained when the cells were triggered with ATP and transient when the response was elicited by TRH or bradykinin. In addition, we have shown that under the appropriate experimental conditions, high thyroid-stimulating hormone (TSH) concentrations were also able to stimulate human thyrocyte IP1, IP2 and IP3 accumulation and to increase their [Ca2+]i. These data suggest that ATP, bradykinin, TRH and high TSH concentrations activate the Ca(2+)-phosphatidylinositol cascade of human thyrocytes. Since this cascade plays a crucial role in the control of protein iodination, ATP, TRH and bradykinin could be important regulators of thyroid hormone synthesis in human thyrocytes.

Effects of inactivity and exercise on bone

SummaryBone mass and muscular mass show a parallel evolution during growth, and parallel involution with age. However, the bone loss related to the withdrawal of oestrogens is independent of muscular waste. The extensive study of disuse osteoporosis shows that exercise without weightbearing cannot counteract the loss of bone mass provoked by bed rest or weightlessness. Physical training, even at low frequency (30 to 60 min/day, 2 or 3 days/week), can increase bone mass or reduce bone loss associated with age. This effect is even present when exercise is practised by very old people at a seemingly low level of muscular tension on bone. It is not known whether muscular exercise could be helpful in pathological osteopenia.Experiments in animals indicate a short-lived benefit of exercise practised during a definite growth period; the long term effect of physical training in humans, after cessation of such activity, has not been studied extensively. Equal distribution of tension on all parts of the skeleton is probably not mandatory to obtain a general effect of exercise on bone mass. It is assumed that muscular exercise acts through tension exerted on bone, but the exact mechanism is unknown, as are the specifications of effective exercise in terms of site of application, intensity, frequency and duration. Moreover, little is known about the expected synergy between exercise and occupational activity.

Carbachol and sodium fluoride, but not TSH, stimulate the generation of inositol phosphates in the dog thyroid

In dog thyroid slices prelabeled with myo‐[2‐3H]inositol, carbachol (10−710−4 M) and NaF (10‐20 mM) stimulated IP1, IP2 and IP3 generation. These effects did not require the presence of extracellular calcium. Atropine and PDBu inhibited the action of the cholinergic agonist. No effect of TSH (1–100 ) could be detected on PIP2 hydrolysis and IP production. These results suggest that (i) IP3 could play a role in the metabolic actions of carbachol in the thyroid; (ii) a G‐protein coupling the hormone‐receptor binding to phospholipase C activation exists in the thyroid membrane; (iii) the well known TSH‐induced increased PI turnover does not result in IP3 accumulation.

Serum triiodothyronine, bone turnover, and bone mass changes in euthyroid pre- and postmenopausal women

SummaryHyperthyroidism and thyroid hormone substitutive therapy with serum iT3 in the normal range of values are known to lead to increased bone remodeling and loss of bone mass. We looked for a relationship between serum iT3 and bone metabolic or bone mass parameters in 402 euthyroid women aged 44–60. In a group of 93 premenopausal women, a group of 309 postmenopausal women, and a group of 118 untreated postmenopausal women, serum iT3 was higher in the women classified as having “high” bone turnover according to both alkaline phosphatases and hydroxyprolinuria values. In postmenopausal women, serum iT3 corrected for thyroid binding globulin (TBG) (T3c) was higher in those receiving no estrogen replacement therapy. In a longitudinal study (n=131), the rate of changes in lumbar bone mineral content was associated with changes in T3c. A less favorable bone mass evolution was associated with an increase in serum T3c, and inversely. Data suggest that the relationship of iT3/bone metabolism is direct and not merely the consequence of estrogen induced changes in both iT3 and bone metabolism. iT3 should be explored at the bone cellular level as a possible mediator in bone metabolic changes occurring in menopause and many other clinical situations.

Thyrotropin does not activate the phosphatidylinositol bisphosphate hydrolyzing phospholipase C in the dog thyroid

The effects of thyrotropin (TSH) and carbamylcholine (Cchol) on labeling by [3H]inositol of inositol lipids (i.e. total phosphoinositides (PI)) and inositol phosphates (IP) and on diacylglycerol (DAG) generation was studied in dog thyroid slices. Both agents (TSH 1-250 mU/ml, Cchol 10(-6) to 10(-4) M) increased the incorporation of [3H]inositol into PI and IP during 4 h labeling experiments; but the [3H]IP/[3H]PI ratio as compared to the control one was not modified by TSH (10 mU/ml: 1.03 +/- 0.24) while it was increased by Cchol (10(-5) M: 6.14 +/- 1.81). Slices prelabeled in the absence of agonists were then incubated in the presence or absence of 10 mM LiCl +/- 10(-4) M inositol. With LiCl alone, Cchol increased [3H]IP generation, while no such effect of TSH could be detected. However, in the absence of LiCl or in the presence of both LiCl and 10(-4) M inositol, TSH and Cchol both increased [3H]PI and [3H]IP, but IP and PI labeling remained strictly proportional with TSH (10 mU/ml: [3H]IP/[3H]PI ratio = 1.03 +/- 0.06 vs. control), while Cchol increased this ratio (10(-5) M = 2.44 +/- 0.24) with a preferential accumulation of IP. Both agonists stimulated DAG formation with similar kinetics and maximal effects (400% of control at 60 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of contrast enhanced three dimensional echocardiography with MIBI gated SPECT for the evaluation of left ventricular function

BackgroundIn clinical practice and in clinical trials, echocardiography and scintigraphy are used the most for the evaluation of global left ejection fraction (LVEF) and left ventricular (LV) volumes. Actually, poor quality imaging and geometrical assumptions are the main limitations of LVEF measured by echocardiography. Contrast agents and 3D echocardiography are new methods that may alleviate these potential limitations.MethodsTherefore we sought to examine the accuracy of contrast 3D echocardiography for the evaluation of LV volumes and LVEF relative to MIBI gated SPECT as an independent reference. In 43 patients addressed for chest pain, contrast 3D echocardiography (RT3DE) and MIBI gated SPECT were prospectively performed on the same day. The accuracy and the variability of LV volumes and LVEF measurements were evaluated.ResultsDue to good endocardial delineation, LV volumes and LVEF measurements by contrast RT3DE were feasible in 99% of the patients. The mean LV end-diastolic volume (LVEDV) of the group by scintigraphy was 143 ± 65 mL and was underestimated by triplane contrast RT3DE (128 ± 60 mL; p < 0.001) and less by full-volume contrast RT3DE (132 ± 62 mL; p < 0.001). Limits of agreement with scintigraphy were similar for triplane andfull-volume, modalities with the best results for full-volume. Results were similar for calculation of LV end-systolic volume (LVESV). The mean LVEF was 44 ± 16% with scintigraphy and was not significantly different with both triplane contrast RT3DE (45 ± 15%) and full-volume contrast RT3DE (45 ± 15%). There was an excellent correlation between two different observers for LVEDV, LVESV and LVEF measurements and inter observer agreement was also good for both contrast RT3DE techniques.ConclusionContrast RT3DE allows an accurate assessment of LVEF compared to the LVEF measured by SPECT, and shows low variability between observers. Although RT3DE triplane provides accurate evaluation of left ventricular function, RT3DE full-volume is superior to triplane modality in patients with suspected coronary artery disease.

Transducing Systems in the Control of Human Thyroid Cell Function, Proliferation and Differentiation

Our laboratory has been involved in the study of thyroid regulation at the cellular level for many years. The complex picture emerging from these studies leads to conclusions of general relevance. The regulation of the thyroid cell was once a classical example of the concept one hormone — one cell type — one intracellular secondary messenger with its pleiotypic effects. It should now rather be considered as a network of crosslinked regulatory steps where the extracellular and intracellular signal-molecules act on their receptors as bits of information in an electronic circuit, i.e., express on/off regulations with no definite general physiological meaning per se. Such networks differ from one cell type to another and for a given cell type from one species to another. In the case of the thyroid many apparent discrepancies in the literature are explained if this is taken into account. In this presentation, we wish to draw mainly on the results of our group to illustrate this point with regard to the regulation of function, proliferation and differentiation of the thyroid cell.

The Control of Human Thyroid Cell Function, Proliferation and Differentiation

The study of thyroid regulation at the cellular level is the main interest of our laboratory since many years. The complex picture emerging from these studies leads to conclusions of general relevance. The regulation of the thyroid cell was once a classical example of the concept one hormone — one cell type — one intracellular secondary messenger with its pleiotypic effects. It should now rather be considered as a network of crosslinked regulatory steps where the extracellular and intracellular signal-molecules act on their receptors as bits of information in an electronic circuit, i.e., express on/off regulations with no definite general physiological meaning per se. Such networks differ from one cell type to another and for a given cell type from one species to another. In the case of the thyroid, many apparent discrepancies in the literature are explained if this is taken into account. In this presentation, we wish to draw mainly on the results of our group to illustrate this point with regard to the regulation of function, proliferation and differentiation of the thyroid cell.