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R Bouillon

Publications and source records attributed to R Bouillon.

At least 109 records · Page 6Linked to original sources
PubMed1998

Anchorage-dependent expression of the vitamin D receptor in normal human keratinocytes.

Although the nuclear vitamin D receptor (VDR) is involved in the control of keratinocyte proliferation and differentiation by its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], its role in epidermal physiology remains poorly understood. Because VDR abundance reflects cellular responsiveness to 1,25(OH)2D3, we investigated VDR expression in cultured human keratinocytes and identified cell anchorage and cytoskeletal integrity as essential requirements for the maintenance of VDR levels. Suspension culture rapidly suppressed VDR expression and 1,25(OH)2D3 responsiveness (as estimated by induction of 24-hydroxylase mRNA), due to decreased transcription of the VDR gene. Concomitantly, overt growth arrest with p21WAF1 induction and cyclin D1 and c-myc suppression occurred, together with induction of differentiation markers and retinoid X receptor alpha, the heterodimeric partner for VDR. Reattachment of suspended keratinocytes to fibronectin led to a rapid restoration of VDR expression, which could be blocked by RGD peptides or a blocking anti-beta1 integrin antibody. VDR expression was also reduced by disruption of the actin cytoskeleton with cytochalasin D. Malignant keratinocytes (SCC12B2 and A431), characterized by, anchorage-independent growth, displayed a profound resistance to suspension-induced suppression of VDR, cyclin D1, and c-myc. Taken together, our results associate VDR expression [and 1,25(OH)2D3 responsiveness] with cell adhesion and an organized cytoskeleton, which are also required for cell growth of primary cells.

Actins↗
PubMed1998

Serum parathyroid hormone and calcium during the first days after resection of a parathyroid adenoma.

Serum parathyroid hormone, calcium and phosphate were daily monitored in 12, 30 and 30 patients respectively during the early postoperative period after removal of a solitary parathyroid adenoma. In all patients PTH concentration dropped to very low values on the first postoperative day, whereafter a rapid recovery began. So the first day is the best time to evaluate the results of the intervention. Hypocalcemia was most frequent on the third day. After ten days 26 patients showed a normal calcemia, while 4 patients still had a mild hypocalcemia (8-8.8 mg/dl). These data may guide management of patients after parathyroid surgery.

Adenoma↗
PubMed1998

Recombinant human interleukin-11 does not modify biochemical parameters of bone remodeling and bone mineral density in adult ovariectomized rats.

Interleukin (IL)-11 stimulates osteoclast formation and inhibits osteoblast function in vitro and has been implicated in estrogen deficiency-induced bone loss. Herein we report the in vivo effect of recombinant human IL-11 (rHU-IL-11), administered s.c. in doses between 10 and 200 microg/kg/day for 6 weeks into 6-month-old rats after ovariectomy. There was no difference between vehicle-treated and rHu-IL-11 treated rats in the ovariectomy-induced increase in the urinary excretion of pyridinoline and deoxypyridinoline. Neither was there a significant effect of rHu-IL-11 on the plasma concentrations of osteocalcin and on bone mineral density (BMD) measured at a metaphyseal area of the distal femur after 6 weeks. At all dosages tested, rHu-IL-11 increased the femoral diaphyseal area. In conclusion, IL-11 has no deleterious in vivo effect on biochemical parameters of bone remodeling and BMD in estrogen-deficient rats.

Amino Acids↗
PubMed1998

Relationship between age-associated endocrine deficiencies and muscle function in elderly women: a cross-sectional study.

OBJECTIVE: Muscle receptors and selected anabolic effects have been identified for both insulin-like growth factor I (IGF-I) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). The aim of the present study was to test the hypothesis that the decreasing concentrations of these endocrine factors might be involved in the decline in muscle function that characterizes normal human ageing. DESIGN: Cross-sectional study. STUDY PARTICIPANTS: A community-based sample of 245 healthy elderly women aged 70-90 years. Exclusion criteria were diseases or medications known to affect muscle function or the somatotrophic axis. MEASUREMENTS: Knee extension strength was evaluated using an isokinetic dynamometer. A standardized questionnaire was used to assess habitual physical activity. IGF-I and 1,25(OH)2D3 were measured by radioimmunoassay. Vitamin D binding protein (DBP) was measured by single radial immunodiffusion and the free 1,25(OH)2D3 concentration calculated as the molar ratio of total 1,25(OH)2D3 to DBP. RESULTS: The differences in isometric and isokinetic strength over the age range were equivalent to losses of 0.9-2.4% per year. However, no relationship was found between the somatotrophic axis or vitamin D status and knee extension strength, despite markedly decreasing concentrations of circulating IGF-I and free 1,25(OH)2D3 with age. CONCLUSION: Levels of circulating IGF-I and free 1,25(OH)2D3 appear not to be involved in the loss of muscle function that characterizes normal human ageing.

Aged↗
PubMed1998

Recent developments in the use of vitamin D analogues.

The activated form of vitamin D3, 1 alpha,25(OH)2D3, not only plays a central role in bone and calcium metabolism, but also has potent antiproliferative and prodifferentiating effects. Moreover, the combined presence of 25(OH)D3-1 alpha-hydroxylase, as well as the vitamin D receptor in several tissues introduced the idea of a paracrine role for 1 alpha,25(OH)2D3. By introducing chemical modifications into the flexible molecule 1 alpha,25(OH)2D3, a whole generation of vitamin D analogues was created. Due to a clear dissociation of the antiproliferative and prodifferentiating effects from calcaemic effects, these analogues can be used not only for the treatment of bone disorders but also for non-classical applications. In the present review, a summary is given on the use of the 1 alpha,25(OH)2D3 analogues for the treatment of psoriasis, cancer and immune disorders together with new insights in the mechanism of action of these analogues.

Animals↗
PubMed1998

Vitamin D and regulation of gene expression.

The function of 1,25-dihydroxyvitamin D3, the biologically active form of vitamin D, extends from bone and mineral homeostasis to the control of cell growth and differentiation in a variety of tissues. Most of these actions are mediated by activation of the nuclear vitamin D receptor, which regulates the transcription of vitamin D target genes. Considerable progress has been made in the understanding of vitamin D receptor function (especially regarding its interaction with coactivators), as well as in the identification of novel vitamin D responsive genes related to cell growth, differentiation and cytokine production.

Animals↗
PubMed1998

5-Hydroxytryptamine-1 receptor activation inhibits endocrine pancreatic secretion in humans.

The selective 5-hydroxytryptamine-1 receptor agonist sumatriptan inhibits exocrine pancreatic function in humans. No data are available on the effect of sumatriptan on fasting and postprandial endocrine pancreatic function in humans. To elucidate the influence of 5-hydroxytryptamine-1 receptor activation by sumatriptan on endocrine pancreatic function and blood glucose homeostasis, we determined plasma levels of somatostatin, glucagon, pancreatic polypeptide, insulin, and C-peptide before and after subcutaneous administration of sumatriptan (6 mg) in seven healthy volunteers, and we measured blood glucose and insulin plasma levels during an oral glucose tolerance test after placebo and after subcutaneous administration of sumatriptan (6 mg) in seven healthy volunteers. Sumatriptan significantly decreased the mean plasma levels of somatostatin, glucagon, pancreatic polypeptide, insulin and C-peptide (P < 0.001) and also significantly decreased mean and peak plasma levels of insulin after an oral glucose challenge (P < 0.02 and P = 0.04, respectively) without affecting glucose homeostasis. From our study, we speculate that activation of the 5-hydroxytryptamine-1 receptor inhibits endocrine pancreatic secretion.

Adult↗
PubMed1998

Prevention of type I diabetes in nonobese diabetic mice by late intervention with nonhypercalcemic analogs of 1,25-dihydroxyvitamin D3 in combination with a short induction course of cyclosporin A.

In nonobese diabetic (NOD) mice, type I diabetes can be prevented without generalized immunosuppression by nonhypercalcemic analogs of vitamin D3 when treatment is started early, i.e. before the autoimmune attack, reflected by insulitis, occurs. The aim of this study was to investigate whether these substances can arrest progression to clinically overt diabetes when administered in a more advanced disease stage, namely when the autoimmune attack is ongoing, reflecting the situation in prediabetic subjects in whom immune intervention is being considered. We, therefore, evaluated the protective potential of MC1288 (20-epi-1,25-dihydroxyvitamin D3) a nonhypercalcemic analog of 1,25-dihydroxyvitamin D3, both alone and in combination with a short induction course of cyclosporin A, in NOD mice that already have insulitis, as demonstrated in pancreatic biopsies performed 15 days before the start oftherapy. Subsequently, mice were randomized into a control group, receiving the treatment vehicle (n = 26), and three treatment groups, receiving, respectively, 7.5 mg/kg x day cyclosporin A (CyA) from days 85-105 (n = 19), 0.1 microg/kg x 2 days MC1288 from days 85-200 (n = 20), or the combination of these two regimens (n = 20). At the time of the pancreatic biopsy (day 70), insulitis was evenly distributed in all groups, and 27.7% of the islets scored showed signs of destructive insulitis. Diabetes outcome by 200 days was 74% (14 of 19) in the CyA-treated group, comparable to the diabetes incidence in control mice (65%; 17 of 26; P = NS). Treatment with MC1288 alone could not reduce disease incidence (70%; 14 of 20), but the combination therapy reduced diabetes incidence to 35% (7 of 20; P < 0.05 vs. untreated; P < 0.01 vs. CyA group; P < 0.025 vs. MC1288). All treatments were well tolerated, without major side-effects on calcium or bone metabolism and without signs of generalized immunosuppression. Cotransfer experiments could not reveal the induction of suppressor cells. Reverse transcription-PCR on pancreatic tissue revealed significantly lower levels of interferon-gamma and higher levels of interleukin-4 in the combination group. In conclusion, nonhypercalcemic analogs of 1,25-dihydroxyvitamin D3 administered to NOD mice when the autoimmune disease is already active can prevent clinical diabetes when this therapy is combined with a short induction course of an immunosuppressant such as CyA.

Animals↗
PubMed1998

Effects of short-term insulin-like growth factor-I (IGF-I) or growth hormone (GH) treatment on bone metabolism and on production of 1,25-dihydroxycholecalciferol in GH-deficient adults.

UNLABELLED: Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 +/- 14 yr of age) were treated with IGF-I (5 micrograms/kg/h in a continuous s.c. infusion) and GH (0.03 IU/kg/daily s.c. injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2-3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. CONCLUSIONS: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1 alpha-hydroxylase activity in vivo.

Adenoma↗
PubMed1998

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Adult↗
PubMed1998

Leptin levels in protracted critical illness: effects of growth hormone-secretagogues and thyrotropin-releasing hormone.

Prolonged critical illness is characterized by feeding-resistant wasting of protein, whereas reesterification, instead of oxidation of fatty acids, allows fat stores to accrue and associate with a low-activity status of the somatotropic and thyrotropic axis, which seems to be partly of hypothalamic origin. To further unravel this paradoxical metabolic condition, and in search of potential therapeutic strategies, we measured serum concentrations of leptin; studied the relationship with body mass index, insulin, cortisol, thyroid hormones, and somatomedins; and documented the effects of hypothalamic releasing factors, in particular, GH-secretagogues and TRH. Twenty adults, critically ill for several weeks and supported with normocaloric, continuously administered parenteral and/or enteral feeding, were studied for 45 h. They had been randomized to receive one of three combinations of peptide infusions, in random order: TRH (one day) and placebo (other day); TRH + GH-releasing peptide (GHRP)-2 and GHRP-2; TRH + GHRH + GHRP-2 and GHRH + GHRP-2. Peptide infusions were started after a 1-microgram/kg bolus at 0900 h and infused (1 microgram/kg.h) until 0600 h the next morning. Serum concentrations of leptin, insulin, cortisol, T4, T3, insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the acid-labile subunit (ALS) were measured at 0900 h, 2100 h, and 0600 h on each of the 2 study days. Baseline leptin levels (mean +/- SEM: 12.4 +/- 2.1 micrograms/L) were independent of body mass index (25 +/- 1 kg/m2), insulin (18.6 +/- 2.9 microIU/mL), cortisol (504 +/- 43 mmol/L), and thyroid hormones (T4: 63 +/- 5 nmol/L, T3: 0.72 +/- 0.08 nmol/L) but correlated positively with circulating levels of IGF-I [86 +/- 6 micrograms/L, determination coefficient (R2) = 0.25] and ALS (7.2 +/- 0.6 mg/L, R2 = 0.32). Infusion of placebo or TRH had no effect on leptin. In contrast, GH-secretagogues elevated leptin levels within 12 h. Infusion of GHRP-2 alone induced a maximal leptin increase of +87% after 24 h, whereas GHRH + GHRP-2 elevated leptin by up to +157% after 24 h. The increase in leptin within 12 h was related (R2 = 0.58) to the substantial rise in insulin. After 45 h, and having reached a plateau, leptin was related to the increased IGF-I (R2 = 0.37). In conclusion, circulating leptin levels during protracted critical illness were linked to the activity state of the GH/IGF-I axis. Stimulating the GH/IGF-I axis with GH-secretagogues increased leptin levels within 12 h. Because leptin may stimulate oxidation of fatty acids, and because GH, IGF-I, and insulin have a protein-sparing effect, GH-secretagogue administration may be expected to result in increased utilization of fat as preferential substrate and to restore protein content in vital tissues and, consequently, has potential as a strategy to reverse the paradoxical metabolic condition of protracted critical illness.

Adult↗
PubMed1998

The biological activity of nonsteroidal vitamin D hormone analogs lacking both the C- and D-rings.

1alpha,25-dihydroxyvitamin D is a key calcium-regulating hormone but also displays potent differentiating and antiproliferative activities on many cell types. The structural requirements of this secosteroid hormone have been extensively studied for the A-ring and side chain, whereas relatively little is known about the requirements of the natural CD-ring structure for the vitamin D-like biological activity. We have embarked on a vast program in which derivatives were synthesized and evaluated characterized by profound structural changes in the central C/D-region. This first series of nonsteroidal analogs consists of (1R,3S)-5-((Z,2E)-4-((1S,3S)-3-(4-hydroxy-4-methylpentyl)-1,2,2-++ +trimethylcyclopentyl)-2-butenylidene)-4-methylenecyclohexan e-1,3-diol (KS 176) and derivatives thereof. These analogs are characterized by the absence of normal C- and D-rings and by the presence of an unnatural five-membered ring which we call the E-ring. KS 176 with the otherwise natural side chain structure of 1alpha,25(OH)2D3 has between 10 and 30% of the biological activity of 1alpha,25(OH)2D3 when tested in vitro (prodifferentiating effects on HL-60 and MG-63; antiproliferating activity on MCF-7 and keratinocytes) but has minimal in vivo calcemic effects. Introduction of several side chain modifications created analogs with increased intrinsic noncalcemic biological properties, whereas their calcemic potency remains very low. These data demonstrate that the full CD-rings are not mandatory for the biological activity of 1alpha,25(OH)2D3 since they can be replaced by a new ring structure which generates an appropriate spacing of the A-seco B-rings in relation to the side chain. The biological activity of these nonsteroidal analogs probably involves a classical genomic activation since they are also active in transfection assays using an osteocalcin vitamin D responsive element coupled to a human growth hormone reporter gene.

Animals↗
PubMed1998

Sex difference in resistance to dexamethasone-induced apoptosis in NOD mice: treatment with 1,25(OH)2D3 restores defect.

The NOD mouse, a model for type 1 diabetes, is characterized by resistance to apoptosis in immunocytes. The aim of this study was to investigate a link between apoptosis in NOD thymocytes and autoimmunity. First, we demonstrated that the sexual dimorphism in diabetes incidence in NOD mice (females are more diabetes-prone than males) is reflected by differences in apoptosis. Apoptosis in NOD thymocytes, 24 h after dexamethasone, was decreased in both sexes compared with C57B1/6, but it was lower in female mice (26 +/- 2%) than in male mice (50 +/- 3%, P < 0.001). Further, we demonstrated that sex hormones themselves play a central role in this difference, since castration of NOD male mice, which increases diabetes incidence, decreased apoptosis levels (32 +/- 2%), while treatment of NOD female mice with dihydrotestosterone, which protects against diabetes, restored apoptosis to male levels (42 +/- 1.5%). Finally, we demonstrated that 1,25-dihydroxyvitamin D3, a steroid hormone that prevents diabetes in NOD mice, restored apoptosis levels to C57B1/6 reference levels. This improved apoptosis was seen in male (68 +/- 1 vs. 50 +/- 3% in untreated NOD mice, P < 0.001) but especially in female NOD mice (51 +/- 5 vs. 26 +/- 2% in untreated NOD mice, P < 0.001). Fluorescence-activated cell sorter analysis of thymocyte subsets revealed marked differences, especially in CD4+CD8+ and CD4+ cells. We conclude that the sexual dimorphism in diabetes incidence in NOD mice is paralleled by a dimorphism in resistance to apoptotic signals in NOD thymocytes. This resistance to apoptosis is driven by sex hormones and is corrected by 1,25-dihydroxyvitamin D3.

Animals↗
PubMed1997

Protection against autoimmune diabetes in mixed bone marrow chimeras: mechanisms involved.

After bone marrow transplantation, complete nonobese diabetic (NOD) into (NOD x C57Bl/10)F1 chimeras developed insulitis in 100% (7/7) and diabetes in 58% (7/12) of cases. In contrast, when mixed chimerism was induced, a near complete protection against insulitis (3/23, p < 0.0001 vs complete chimeras) and diabetes (0/25, p < 0.001 vs complete chimeras) was achieved even in chimeras with as few as 5% F1 cells. In cotransfer experiments, splenocytes from mixed chimeras failed to prevent diabetes, thus overruling a role for suppressor cells in protection. Whereas splenocytes from complete chimeras transferred diabetes into young irradiated NOD mice in all cases, NOD splenocytes from mixed chimeras only rarely transferred diabetes (3/16, p < 0.01 vs complete chimeras), suggesting that the latter cells had developed tolerance toward beta cells. To achieve this tolerance, the presence of an F1 thymus was not needed. Indeed, whereas splenocytes isolated from complete chimeras were diabetogenic when transferred into neonatally thymectomized irradiated NOD recipients (3/4), they failed to induce diabetes when transferred into neonatally thymectomized irradiated F1 recipients in case again a state of mixed chimerism was induced (0/4, p < 0.001 vs NOD recipients). Finally, a role for non-MHC Ags was demonstrated by experiments in F1 mice crossed between NOD and C57Bl/6, a strain congenic to C57Bl/10. Here protection against disease was only seen in the presence of high levels of F1 cells (>25%). In conclusion, mixed bone marrow chimerism can induce self-tolerance in autoimmunity prone NOD immune cells. This can be achieved extrathymically but may depend on non-MHC Ags and the level of chimerism.

Adoptive Transfer↗
PubMed1997

Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.

Mutations in the vitamin D receptor (VDR) result in target organ resistance to 1alpha,25-dihydroxyvitamin D [1,25(OH)2D3], the active form of vitamin D, and cause hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR). We analyzed the VDR of a patient who exhibited three genetic diseases: HVDRR, congenital total lipodystrophy, and persistent mullerian duct syndrome. The patient was treated with extremely high dose calcitriol (12.5 microg/d) which normalized serum calcium and improved his rickets. Analysis of [3H]1,25(OH)2D3 binding in the patient's cultured fibroblasts showed normal abundance of VDR with only a slight decrease in binding affinity compared to normal fibroblasts when measured at 0 degrees C. The patient's fibroblasts demonstrated 1,25(OH)2D3-induction of 24-hydroxylase mRNA, but the effective dose was approximately fivefold higher than in control cells. Sequence analysis of the patient's VDR gene uncovered a single point mutation, H305Q. The recreated mutant VDR was transfected into COS-7 cells where it was 5 to 10-fold less responsive to 1,25(OH)2D3 in gene transactivation. The mutant VDR had an eightfold lower affinity for [3H]1,25(OH)2D3 than the normal VDR when measured at 24 degrees C. RFLP demonstrated that the patient was homozygous for the mutation while the parents were heterozygous. In conclusion, we describe a new ligand binding domain mutation in the VDR that causes HVDRR due to decreased affinity for 1,25(OH)2D3 which can be effectively treated with extremely high doses of hormone.

Calcitriol↗
PubMed1997

Biochemical and density assessment of the new bone in late remodeling after callus distraction.

Biochemical changes in a canine bone-lengthening model were characterized 5 months after surgery. The mineral content and the total amount of EDTA-extractable noncollagenous proteins, insulin-like growth factor-I, and osteocalcin were determined for the lengthened callus, and a gradient density fractionation analysis of bone powder particles was performed. The results were compared with two other areas of the lengthened tibia and one region of the contralateral tibia. The mineral and osteocalcin contents showed significant decreases, whereas the hydroxyproline concentration was significantly increased. Neither the insulin-like growth factor-I content nor the concentration of EDTA-extractable proteins was significantly different in any of the examined regions.

Animals↗