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A Dutour

Publications and source records attributed to A Dutour.

At least 19 recordsLinked to original sources
PubMed2006

11beta-Hydroxysteroid dehydrogenase type 1-driven cortisone reactivation regulates plasminogen activator inhibitor type 1 in adipose tissue of obese women.

BACKGROUND: Plasminogen activator inhibitor type 1 (PAI-1) is the main inhibitor of the fibrinolytic system and contributes to an increased risk of atherothrombosis in insulin-resistant obese patients. In adipose tissue, we have shown that PAI-1 is synthesized mainly in the visceral stromal compartment and is positively regulated by glucocorticoids. We have demonstrated that adipose tissue expression of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is exaggerated in obese patients. OBJECTIVES: We hypothesized that increased action of 11beta-HSD-1 in adipose tissue of obese subjects may contribute to PAI-1 overproduction. PATIENTS AND METHODS: Using in situ hybridization, we studied the expression of the mRNAs coding for PAI-1 and 11beta-HSD-1 in the stromal compartment of visceral adipose tissue obtained from obese women. The regulation of PAI-1 secretion from in vitro incubated tissue explants was also investigated. RESULTS: Regression analysis showed a significant positive linear relationship between PAI-1 and 11beta-HSD-1 mRNAs expression. In vitro incubation of adipose tissue explants demonstrated that cortisone stimulated PAI-1 gene expression and secretion, and that these effects were inhibited by co-incubation with the 11beta-HSD inhibitor, glycyrrhetinic acid. CONCLUSIONS: Our data demonstrate that 11beta-HSD-1-driven cortisone reactivation regulates adipose PAI-1 synthesis and secretion. They suggest that the increased PAI-1 synthesis and secretion observed in obese patients can be also related, at least in part, to an increased local conversion of cortisone to cortisol. Therefore, local cortisol metabolism in adipose tissue may be involved in increasing the risk of cardiovascular disease in obese subjects.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2004

Alterations of somatotropic function in prion disease in sheep.

This study aimed at investigating the possible linkage between natural scrapie and alterations of the somatotropic axis. Scrapie-affected ewes exhibited 2-fold higher mean GH concentrations during both autumn and spring. GH pulse frequencies were higher in scrapie-affected ewes than in control animals (mean+/-S.E.M. number of pulses/24 h: 10.4+/-0.9 and 7.6+/-0.9 for scrapie-affected and control ewes respectively) suggesting the involvement of central mechanisms. GH secretion induced by administration of an alpha(2)-adrenergic agonist, which acts centrally to stimulate GH secretion, was similar between healthy and scrapie-affected ewes (ratios of the area under the curve (AUC) of GH concentration after to the GH AUC before the agonist administration were 3.6+/-1.6 and 4.9+/-1.0 for scrapie-affected and control ewes respectively). Finally, humoral markers and parameters of the metabolic status were determined to test the hypothesis that scrapie-associated alterations of GH secretion could be related to disruption of metabolic homeostasis. Glucose, insulin and urea plasma concentrations were higher in scrapie-affected than in healthy ewes. Neither leptin nor IGF-I levels were affected by scrapie. Total thyroxine (T4) was decreased in scrapie-affected ewes but free T4 and total and free triiodothyronine were not modified. In conclusion, our results showed the existence in scrapie-affected ewes of endocrine and metabolic alterations typical of acute illness proceeding, at least in part, from central mechanisms.

Acute Disease↗
PubMed2002

Molecular cloning and tissue distribution of the ovine somatostatin receptor subtype 5: osst5.

The sheep is a valuable model to study growth hormone (GH) neuroregulation since its GH secretion pattern is close to that in humans and an integrated physiological approach is possible in this species. Somatostatin receptor subtype 5 (sst5) appears to be important in GH regulation but the ovine sst5 gene (osst5) has not yet been cloned. We report here the cloning of sst5 in that species. We screened a cDNA sheep library and isolated a 1.24 kb cDNA, which includes the whole coding region of osst5. The predicted protein consists of 367 amino acids exhibiting a putative seven transmembrane domain topology typical of G protein-coupled receptors. Nucleotide sequence comparisons with that of other species sst5 showed that osst5 displays 83.8, 81 and 79.7% homology with human, rat, and mice sst5, respectively. Southern blot analysis of ovine cortex DNA demonstrated that osst5 is encoded by a single gene. Osst5 transiently expressed in Chinese Hamster ovary (CHO) cells exhibit a high affinity for somatostatin-14. Reverse transcriptase-polymerase chain reaction (RT-PCR) studies demonstrated that osst5 mRNAs are present in pituitary, cortex, hypothalamus, hippocampus, colon and adrenal gland. The cloning of osst5 should provide a useful tool to study the mechanisms through which somatostatin inhibits hormone secretion in the sheep.

Adrenal Glands↗
PubMed2001

The ovine somatostatin receptor subtype 1 (osst1): partial cloning and tissue distribution.

The sheep is a valuable model to study GH neuroregulation since its GH secretion pattern is close to that in human. Somatostatin receptor subtype 1 (sst1) appears to be important in central regulation of GH but ovine sst1 (osst1) has not yet been cloned. We report here the cloning of the major part of sst1 in that species. Using human primers from transmembrane domain 2 and 7, we amplified from sheep tissue by RT-PCR a 700 bp fragment. By screening a cDNA sheep library with this fragment, we isolated a 1.4 kb cDNA which contained the major part of the coding cDNA of osst1. The partial predicted protein consists of 347 amino acids exhibiting a putative seven transmembrane domain topology typical of G protein-coupled receptors. Nucleotide sequence comparisons with that of other species showed that osst1 displays 88% homology with human sst1, 84% with rat sst1 and 87% with mouse sst1. Southern blot analysis of ovine cortex DNA demonstrated that osst1 is encoded by a single gene. Northern blot studies evidenced a 3.9 kb transcript highly expressed in the cortex and the hippocampus. This transcript was also present in hypothalamus, striatum, cerebellum, olfactory bulb, spinal cord, brain stem, the lung, kidney, liver, adrenal glands and at a low level in the pituitary gland. No signal was noticeable in the pineal gland. The sequence homology, the tissue distribution, the length of the transcript link this cDNA to the somatostatin receptor family and particularly to sst1.

Amino Acid Sequence↗
PubMed2000

Increased expression of the mRNA encoding the somatostatin receptor subtype five in human colorectal adenocarcinoma.

Numerous studies have suggested that the antiproliferative potency of somatostatin (SS) analogues may be an efficient tool to improve the prognosis of colorectal cancer. In order to facilitate current efforts to design potent antitumour SS analogues, we studied the distribution of human SS receptors (hsst1-5) mRNAs in a large set of tumoural and normal colonic tissues. Localisation of hsst1-5 mRNAs in normal and tumoural tissues was performed by in situ hybridisation using radioactive antisense or sense riboprobes. Semi-quantitative analysis of hsst5 mRNA was performed using a computerised image analysis system. Hsst binding sites were characterised by studying the relative potency of SS14, SS28 or SS analogues in displacing [(125)I]Tyr degrees -d-Trp(8)-SS14 bound to HT29-D4 cells. Hsst5 mRNA was by far the most expressed subtype in both normal and transformed epithelial cells as well as in the HT29-D4 cell line. An increased expression of hsst5 mRNA was found in tumours. Hsst1 mRNA was expressed preferentially as clusters in immune cells in lamina propria and in stroma close to the tumour. A low expression of hsst4, hsst3 and hsst2 was seen in normal and tumoural tissue. In HT29-D4, binding experiments with SS14 demonstrated the existence of one SS binding class (K(d)=524 nM, B(max)=1fmol/10(6 )cells). In competition binding studies, SS28 and BIM23268 (an analogue that shows preferential specificity towards hsst5) effectively inhibited binding of [(125)I]Tyr degrees -d-Trp(8)-SS14 (IC(50)=15 and 157 nM respectively), while BIM23197 (an analogue that shows preferential affinity for hsst2) was ineffective. Our results show a high expression of hsst5 mRNA in human tumoural colonic tissue, while hsst5 protein is the predominant hsst protein subtype in a tumoural colonic cell line.

Adenocarcinoma↗
PubMed2000

IGF-I/IGFBPs system response to endotoxin challenge in sheep.

Endotoxin (LPS), a membrane component of gram-negative bacteria produces multiple endocrine and metabolic effects that mimic those seen in acute sepsis. It induces species-dependent alterations of the growth hormone (GH) axis that may participate in the shift of the metabolism towards catabolic events. Humans and sheep show increased GH secretion in response to LPS, as opposed to rats, which have been the most studied. The purpose of our work was to evaluate the effects in intact rams of an acute intravenous administration of a high dose of LPS on the insulin-like growth factor (IGF)-I/IGF-binding proteins (IGFBPs) system and to analyse the temporal relationship of GH axis changes with those of several hormonal and metabolic parameters such as somatostatin, cortisol, insulin, and glucose. LPS induced a late moderate decrease of total IGF-I plasma levels following a 5-h steady-state period (-26.6+/-4. 2%, P<0.05, 9 h after LPS), despite a biphasic and sustained increase of GH secretion in the same animals (2.48+/-0.39 ng/ml 2 h after LPS and 2.7+/-0.37 ng/ml 5 h after LPS vs 0.77+/-0.10 before LPS; Briard et al. 1998a). Western ligand blot analysis in IGFBPs showed an early short-lasting increase in IGFBP-1 (188.8+/-39% P<0. 05, 3 h after LPS). No significant change was seen for either IGFBP-2, -3 or -4. We observed a marked and sustained increase in cortisol (128.18+/-7.21 ng/ml 3 h after LPS, vs 21.17+/-4.22 before LPS). Insulin also increased (27.69+/-3.90 microU/ml 3 h after LPS, vs 13.48+/-1.69 before LPS) and its burst coincided with that of IGFBP-1. Moderately decreased IGF-I and increased IGFBP-1 plasma levels contrasted with the sustained increase in GH secretion that we recently described, thereby suggesting that endotoxin causes a state of resistance to GH. This may be exacerbated by reduced IGF-I bioavailability and/or action, and which may participate in the pathophysiology of the catabolic state seen in sepsis. The temporal analysis of hormone responses suggests that endotoxin-induced alterations of the IGF-I/IGFBPs system may involve the prolonged and substantial somatostatin rise that we recently demonstrated, together with an increase in glucocorticoid and cytokine as more generally assumed.

Animals↗
PubMed1999

Myelofibrosis: an unusual presentation of vitamin D-deficient rickets.

UNLABELLED: We present the case of a breast-fed 5-month-old infant who presented with pancytopenia, secondary to intense myelofibrosis during the winter months because of undiagnosed rickets. The patient responded to oral vitamin D with rapid resolution of symptoms. Secondary hyperparathyroidism was the probable cause of the myelofibrosis. CONCLUSION: Although nutritional rickets remains a problem in developing countries, children in northern climates in industrialized countries may also be at risk. Rickets must be considered when assessing myelofibrosis in a very young child.

Humans↗
PubMed1999

On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis.

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

Adrenocorticotropic Hormone↗
PubMed1999

No loss of sst receptors gene expression in advanced stages of colorectal cancer.

As demonstrated by several studies, the pan-inhibitory peptide somatostatin (SS) is implicated in a large variety of physiological processes in the gastrointestinal tractus. SS inhibits hormonal and gastric acid secretions, and decreases gastric and intestinal motility, mesenteric blood flow and intestinal absorption. In vitro and in vivo studies showed also that the antiproliferative potency of SS analogs may be a target to improve the prognosis of colorectal cancer. Here we report the expression profile of the five SS receptor subtypes (hsst1-5) mRNAs in a large set of tumoral and normal colon. Using reverse transcription-PCR, we showed that hsst5, hsst1 and hsst2 mRNA subtypes were the most frequently expressed hsst mRNA subtypes in normal and pathological colon. Interestingly, we found that the frequency of hsst5 mRNA expression in the left colon was significantly higher in tumors than in normal samples: 81. 2% (13/16) and 36.4% (4/11) respectively (0.025>P>0.01, chi2 test with Yates' correction). We did not find any influence of Dukes' stage on hsst mRNAs expression. Of interest, no loss of hsst2 and hsst5 mRNA expression in advanced stages was noted. Some differences in the frequency of expression of hsst mRNAs according to the origin of the tissue (left or right colon) were evident. The expression of hsst5 and hsst2 mRNA in advanced colorectal carcinoma associated with the development of new SS analogs boost the relevance of colorectal cancer treatment by somatostatin analogs.

Aged↗
PubMed1998

Expression of somatostatin receptor subtypes in human brain tumors.

Expression of mRNA for the 5 somatostatin receptors (sst1-5) was characterized by Northern blot and RT-PCR analysis in 20 meningioma and 9 glioma samples. sst1 mRNA was detectable by Northern blots of poly-A+ RNA in meningiomas but not gliomas. In contrast, sst2 mRNA was readily detected by Northern blots of total RNA as a major 2.3 kb transcript and 2 minor 4.3 kb and 8 kb transcripts in all meningiomas and 6 out of 9 gliomas. Quantitation of the 2.3 kb sst2 mRNA showed that 15 out of 20 tumors expressed 1.3- to 33-fold higher levels than control normal human brain. Mean sst2 mRNA for the 20 meningioma samples was 978% that of normal brain. Three gliomas showed 7- to 14-fold higher sst2 mRNA than normal brain whereas the remaining samples displayed very low or undetectable levels. Immunocytochemistry of meningioma and glioma samples, with a sst2-specific antibody revealed immunoreactivity in tumor cells and peritumoral tissue, with prominent expression in blood vessels. mRNA for sst3,4,5 could not be detected by Northern blots in any of the tumors. RT-PCR analysis of meningiomas and gliomas revealed the following percent of tumors positive for a given sst mRNA: sst1 (86%), sst2 (100%), sst3 (60%), sst4 (58%), and sst5 (67%); 85% of tumors expressed 3 of the 5 subtypes. No correlation was found between the pattern of expression of sst mRNA and tumor type, location, and histology for either the meningiomas or gliomas. Our results show that meningiomas and gliomas are all positive for at least one sst subtype, the majority expressing multiple subtypes. sst2 is the most abundant isoform with a rich expression in both tumor and peritumoral tissue especially blood vessels.

Adult↗
PubMed1998

Refinement of genetic localization of the Alström syndrome on chromosome 2p12-13 by linkage analysis in a North African family.

Alström syndrome is a rare autosomal recessive disorder characterized by retinal pigment degeneration, neurogenic deafness, infantile obesity, hyperlipidemia, and non-insulin-dependent diabetes mellitus. While the disease-related gene remains unknown, studies of the genetic isolate of French Acadians provisionally locate the Alström syndrome on chromosome 2p12-13 within a 14.9-cM interval. To confirm this finding in another ethnic population and refine the candidate region we investigated by linkage analysis a consanguineous family of North African origin, in which three of seven siblings displayed all major neurological and metabolic features of Alström syndrome. Genotyping was performed on an ABI377 DNA automatic sequencer and LOD scores were obtained with the Fastlink program. Five markers previously investigated in French Acadians confirmed the involvement of the candidate region, although pairwise LOD scores were of poor significance (Zmax = 2.9). To further confirm homogeneity and refine the candidate region, 20 additional markers were investigated. Haplotype analysis and allele segregation revealed that affected children shared a single haplotype and were homozygous for the eight most centromeric markers (D2S291-D2S2114), over a 6.1-cM interval. Significative multipoint LOD scores (Zmax = 3.96) were obtained between markers D2S2110/145 and D2S286. Two clusters of known genes are present in this refined region of chromosome 2p, the most attractive candidate being the hexokinase II gene. However, except for several known polymorphisms, no mutations were detected in the coding region of this gene. In conclusion, the location of Alström syndrome on chromosome 2p12-13 is confirmed, reducing the genetic interval to 6.1 cM.

Abnormalities, Multiple↗
PubMed1998

Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep.

Experimental data suggest that elevated FFA levels play a leading role in the impaired GH secretion in obesity and may therefore contribute to the maintenance of overweight. GH has a direct lipolytic effect on adipose tissue; in turn, FFA elevation markedly reduces GH secretion. This suggests the existence of a classical endocrine feedback loop between FFA and GH secretion. However, the FFA mechanism of action is not yet understood. The involvement of somatostatin (SRIH) is controversial, and in vitro experiments suggest a direct effect of FFA on the pituitary. In sheep it is possible to collect hypophysial portal blood and quantify SRIH secretion in hypophysial portal blood under physiological conscious and unstressed conditions. In this study we determined the effects of FFA (Intralipid and heparin) infusion on peripheral GH and portal SRIH levels in intact rams chronically implanted with perihypophysial cannula and in rams actively immunized against SRIH to further determine SRIH-mediated FFA effects on GH axis. Immediately after initiation of Intralipid infusion, we observed a marked increase in the FFA concentration (2160 +/- 200 vs. 295 +/- 28 nmol/ml; P < 0.01) as well as a significant decrease in basal GH secretion (1.8 +/- 0.1 vs. 2.5 +/- 0.3 ng/ml; P < 0.05) and a drastic reduction of the GH response to i.v. GH-releasing hormone injection (4.8 +/- 0.7 ng/ml in FFA group vs. 35.8 +/- 9.7 ng/ml in saline group; P < 0.01). No change in plasma insulin-like growth factor I levels was observed. During the first 2 h of infusion, the GH decrease observed was concomitant with a significant increase in portal SRIH levels (22.1 +/- .2 vs. 13 +/- 1.6 pg/ml; P < 0.01). In rams actively immunized against SRIH, the effect of FFA on basal GH secretion was biphasic. During the first 90 min of infusion, the decrease in GH induced by FFA was significantly blunted in rams actively immunized against SRIH (57 +/- 9% for immunized rams vs. 23.5 +/- 2.5% for control rams). This corresponds to the period of increased SRIH portal levels. After this first 90-min period, no difference was seen between control and immunized rams. Our results show that FFA exert their inhibitory action on the GH axis at both pituitary and hypothalamic levels, the latter mainly during the first 90 min, through increased SRIH secretion.

Animals↗
PubMed1998

Endotoxin injection increases growth hormone and somatostatin secretion in sheep.

Endotoxin has been shown to stimulate GH secretion in human and sheep. However, changes in hypothalamic neurohormones involved in the GH regulation by endotoxin have never been studied in vivo. In sheep it is possible to collect hypophysial portal blood (HPB) and quantify GH-releasing hormone (GHRH) and somatostatin (SRIH) secretion under physiological conditions. The purpose of this study was to determine the effect of an acute i.v. endotoxin administration on the secretion of these peptides in sheep. Endotoxin induced a sustained increase of GH (x6.2 +/- 1.3) in intact rams. This stimulation was delayed and less marked when compared with the hypothalamic-pituitary-adrenal axis. Surprisingly, the GH increase was associated with an important rise of jugular (x10.6 +/- 2.4) and portal (x7.9 +/- 3) SRIH levels, without a significant GHRH increase. To determine if the portal SRIH increase was a consequence of an increased short feedback of GH, we studied GH response to endotoxin after a previous GHRH injection to deplete the pituitary pools of GH. In that case, despite the absence of increase of GH after endotoxin treatment, SRIH levels was markedly increased. For the first time we have observed an experimental situation in sheep with a simultaneous and closed amplitude increase in jugular and portal SRIH. The source of jugular SRIH is likely the gastrointestinal tract and the increased jugular SRIH release in systemic circulation might be in part responsible for the increase of hypophysial portal SRIH. Ultimately our results show that endotoxin induced a complex reaction at multiple levels with a specific increase in both portal and peripheral SRIH levels. The surprising association of a lack of change in GHRH release and an increased secretion of SRIH with the increase of GH suggests that the effect of endotoxin on GH axis is mainly a pituitary one. The selective blockade of somatostatin should be useful for a better knowledge of the role of SRIH stimulation in the physiopathology of septic shock.

Adrenocorticotropic Hormone↗
PubMed1998

Diabetic mastopathy, complication of type 1 diabetes mellitus: report of two cases and a review of the literature.

The breast is not classically included among the organs damaged by diabetic complications. The first cases of breast lesions associated with Type 1 diabetes mellitus were only described in 1984. The disease, designated as diabetic or fibrous mastopathy, is benign but may clinically simulate breast carcinoma. Its frequency is difficult to evaluate, and its pathogenesis is not yet clearly understood. We report two cases of diabetic mastopathy, together with a review of the medical literature on this subject and a description of the main characteristics of the disease. Diagnosis is based on the clinical context (premenopausal women with longstanding Type 1 diabetes mellitus who develop a hard, painless, mobile lump on one or both breasts), radiology (dense glandular tissue on mammography and marked acoustical shadowing of sound waves on sonography), and histopathology (fibrosis and perivascular and periductal lymphocytic infiltration).

Adult↗