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Biomedical subjects

G Brabant

Publications and source records attributed to G Brabant.

At least 109 records · Page 6Linked to original sources
PubMed1996

Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study.

We studied the effects of recombinant growth hormone on systemic nitric oxide (NO) formation and hemodynamics in a double-blind, placebo-controlled trial in adult patients with acquired growth hormone deficiency. 30 patients were randomly allocated to either recombinant human growth hormone (r-hGH; 2.0 IU/d) or placebo for 12 mo. In the subsequent 12 mo, the study was continued with both groups of patients receiving r-hGH. In months 1, 3, 6, 9, and 12 of each year, urine and plasma samples were collected for the determination of urinary nitrate and cyclic GMP as indices of systemic NO production, and of plasma IGF-1 levels. Cardiac output was measured in months 1, 12, and 24 by echocardiography. r-hGH induced a fourfold increase in plasma IGF-1 concentrations within the first month of treatment. Urinary nitrate and cyclic GMP excretion rates were low at baseline in growth hormone-deficient patients (nitrate, 96.8+/-7.4 micromol/mmol creatinine; cyclic GMP, 63.6+/-7.1 nmol/mmol creatinine) as compared with healthy controls (nitrate, 167.3+/-7.5 micromol/mmol creatinine; cyclic GMP, 155.2+/-6.9 nmol/mmol creatinine). These indices of NO production were significantly increased by r-hGH, within the first 12 mo in the GH group, and within the second 12 mo in the placebo group. While systolic and diastolic blood pressure were not significantly altered by r-hGH, cardiac output significantly increased by 30-40%, and total peripheral resistance decreased by approximately 30% in both groups when they were assigned to r-hGH treatment. In the second study year, when both groups were given r-hGH, there were no significant differences in plasma IGF-1, urinary nitrate, or cyclic GMP excretion, or hemodynamic parameters between both groups. In conclusion, systemic NO formation is decreased in untreated growth hormone-deficient patients. Treatment with recombinant human growth hormone normalizes urinary nitrate and cyclic GMP excretion, possibly via IGF-1 stimulation of endothelial NO formation, and concomitantly decreases peripheral arterial resistance. Increased NO formation may be one reason for improved cardiovascular performance of patients with acquired hypopituitarism during growth hormone therapy.

Adult↗
PubMed1996

Self-organized segmentation of time series: separating growth hormone secretion in acromegaly from normal controls.

The pulsatile pattern of growth hormone (GH) secretion was assessed by sampling blood every 10 min over 24 h in healthy subjects (n = 10) under normal food intake and under fasting conditions (n = 6) and in patients with a GH-producing tumor (acromegaly, n = 6), before and after treatment with the somatostatin analog octreotide. Using autocorrelation, we found no consistent separation in the temporal dynamics of GH secretion in healthy controls and acromegalic patients. Time series prediction based on a single neural network has recently been demonstrated to separate the secretory dynamics of parathyroid hormone in healthy controls from osteoporotic patients. To better distinguish the differences in GH dynamics in healthy subjects and patients, we tested time series predictions based on a single neural network and a more refined system of multiple neural networks acting in parallel (adaptive mixtures of local experts). Both approaches significantly separated GH dynamics under the various conditions. By performing a self-organized segmentation of the alternating phases of secretory bursts and quiescence of GH, we significantly improved the performance of the multiple network system over that of the single network. It thus may represent a potential tool for characterizing alterations of the dynamic regulation associated with diseased states.

Acromegaly↗
PubMed1996

Generation of repetitive Ca2+ transients by bombesin requires intracellular release and influx of Ca2+ through voltage-dependent and voltage independent channels in single HIT cells.

In the present study, the bombesin-induced changes in cytosolic free Ca2+ ([Ca2+]i) were investigated in single Fura-2 loaded SV-40 transformed hamster beta-cells (HIT). Bombesin (50-500 pM) caused frequency-modulated repetitive Ca2+ transients. The average frequency of the Ca2+ transients induced by bombesin (200 pM) was 0.58 +/- 0.02 min-1 (n = 121 cells). High concentrations of bombesin (> or = 2 nM) triggered a large initial Ca2+ transient followed by a sustained plateau or by a decrease to basal levels. In Ca(2+)- free medium, bombesin caused only one or two Ca2+ transients and withdrawal of extracellular Ca2+ abolished the Ca2+ transients. The voltage-dependent Ca2+ channel (VDCC) blockers, verapamil (50 microM) and nifedipine (10 microM), reduced amplitude and frequency of the Ca2+ transients and stopped the Ca2+ transients in some cells. Thapsigargin caused a sustained rise in [Ca2+]i in the presence of extracellular Ca2+ while in its absence the rise in [Ca2+]i was transient. Verapamil (50 microM) inhibited the thapsigargin-induced increase in [Ca2+]i by about 50%. Depletion of intracellular Ca2+ stores by repetitive stimulation with increasing concentrations of bombesin or thapsigargin in Ca(2+)-free medium caused an agonist-independent increase in [Ca2+]i when extracellular Ca2+ was restored, which was larger than in control cells that had been incubated in Ca(2+)-free medium for the same period of time. This rise in [Ca2+]i and the thapsigargin-induced increase in [Ca2+]i were only partly inhibited by VDCC-blockers. Thus, depletion of the agonist-sensitive Ca2+ pool enhances Ca2+ influx through VDCC and voltage-independent Ca2+ channels (VICC). In conclusion, the bombesin-induced Ca2+ response in single HIT cells is periodic in nature with frequency-modulated repetitive Ca2+ transients. Intracellular Ca2+ is mobilized during each Ca2+ transient, but Ca2+ influx through VDCC and VICC is required for maintaining the sustained nature of the Ca2+ response. Ca2+ influx in whole or part is activated by a capacitative Ca2+ entry mechanism.

Animals↗
PubMed1996

Radioimmunoassay for the detection of leptin in human serum.

Human leptin, which is encoded by the obese (ob) gene, is secreted specifically from adipocytes and is involved in the regulation of satiety and energy consumption. We developed a radioimmunoassay for the determination of leptin in human serum using polyclonal antibodies generated in rabbits against a C-terminal fragment of leptin, leptin(126-140), coupled to hemocyanin. The sensitivity of the assay was app. 5 pmol/l leptin(126-140) equivalent to 0.5 fmol/tube. The intra-assay variation at 100 pmol/l was less than 4.8% and the interassay variation less than 8.3%. Dilution curves of serum samples containing high levels of leptin(126-140) were parallel to the standard curve. Following G-50 Sephadex chromatography a single specific peak was detected at app. 16 kd. The assay procedure compared well to a commercially available assay (Linco, St. Louis, USA) using polyclonal antibodies directed against the intact recombinant protein (R = 0.96; p < 0.0001). Serum levels were significantly higher than plasma levels (app.20%) over a wide range of the standard curve. Levels of serum leptin126-140 immunoreactivity were not altered by meals and no day-to-day variation was found. In a group of 148 healthy female and 108 healthy male subjects with a BMI between 18.2 and 40 kg/m2 there was a significant difference between sexes with higher circulating serum levels in female than in male subjects when tested for identical BMI (p < 0.001). Serum leptin levels in both male and female subjects were positively related to BMI (p < 0.001) when analysed for lean and obese subjects whereas in lean subjects this relation was not apparent. No relation of serum leptin levels and age was detectable in subjects with a BMI up to 30 kg/m2. These data support an important role of leptin in the regulation of body fat stores and BMI which is modulated by gender specific factors.

Adult↗
PubMed1996

Continuous vs. pulsatile administration of thyrotropin-releasing hormone (TRH) in the model of the chronically cannulated rat: long-term effects on thyroid function.

Thyroid-stimulating hormone (TSH) belongs to a family of glycoprotein hormones secreted by the anterior lobe of the pituitary gland in a pulsatile fashion. Although this pulsatile pattern of release has been characterized by several groups, its exact physiological relevance remains to be elucidated. We established a model of a chronically cannulated rat allowing us to apply quantified pulses of thyrotropin-releasing hormone intravenously and to monitor the biological response on the anterior pituitary as well as on the thyroid level. Serum rTSH, T3 and T4 levels were measured as functional parameters. During the five day infusion period, TSH increased under both continuous and pulsatile TRH stimulation, but this increase was only maintained following pulsatile TRH but not after continuous application. No differences between the continuous and the pulsatile infusion regimen could be observed in terms of TT3 release, whereas TT4 decreased following an initial stimulation under continuous application, but remained stimulated during pulsatile application. Our data indicate that the model of the chronically cannulated rat appears to be a valuable tool to study the impact of the temporal pattern of TRH/TSH on thyroid physiology.

Animals↗
PubMed1996

Cell adhesion receptors and gap junctions in normal and neoplastic transformed thyrocytes.

In the thyroid cell adhesion receptors and gap junctions establish a complex modular network defining the structural properties of cells, their interactions with neighboring cells and the extracellular matrix. Neoplastic alterations of this network can lead to an imbalance of cell to cell communication and allows transformed cells to escape from the tissue to generate metastases. The present manuscript summarizes general and thyroid-specific aspects of the molecular basis of cell-cell contacts, an expanding field of tumor biology.

Animals↗
PubMed1996

Serum leptin levels following hypothalamic surgery.

To study a potential alteration of hypothalamic centers involved in the negative feedback action of leptin on body weight, serum leptin levels were measured in relation to BMI in 18 patients following surgery for a hypothalamic craniopharyngioma (Ctx), and were compared to levels found in 21 patients operated for a pituitary adenoma (Ptx) or in healthy control subjects. All subjects with Ptx received rhGH replacement therapy (0.5 to 2 IU/m2/d), and serum leptin levels were followed in 3 months intervals over 24 months. Serum leptin levels in patients with Ptx were comparable to controls, whereas 7 of the 18 patients with Ctx had higher than expected concentrations for their BMI. GH treatment in Ptx subjects did not alter serum leptin levels. In 5 Ctx patients where preoperative samples were available, weight gain in parallel to an increase in serum leptin levels was observed but only minimal changes in 4 others. Our data support the role of leptin as an important marker of body weight. The rapid increase in serum leptin levels observed in some Ctx subjects suggests that early postoperative measurement of serum leptin levels may help to identify patients at risk of weight gain following hypothalamic destruction.

Adenoma↗
PubMed1996

Acarbose reduces elevated testosterone serum concentrations in hyperinsulinaemic premenopausal women: a pilot study.

In seven hyperinsulinaemic, hypertestosteronaemic premenopausal patients, we tested the effect of an attenuation of insulin serum concentrations by long-term treatment with the enteral disaccharidase inhibitor acarbose on serum concentrations of total and free testosterone, dehydroepiandrosterone sulphate (DHEAS) and sex hormone-binding globulin (SHBG). The subjects showed typical features of hyperinsulinaemia-hypertestosteronaemia syndrome, including elevated concentrations of insulin and testosterone, normal concentrations of DHEAS and suppressed SHBG concentrations. The patients were orally treated with an initial dosage of 50 mg acarbose/ day, which was gradually increased to a maximum of 300 mg/day. Blood was sampled at week 6 (under a dosage of 150 mg acarbose/day) and at week 20 of treatment. A significant reduction in the increase of glucose and insulin concentrations, determined after administration of a standard oral 100 g glucose load, was found at week 6 (P < 0.02, P < 0.00007) and at week 20 (P < 0.04, P < 0.003) of therapy and was associated with a significant decrease of total and free testosterone at week 20 (P < 0.04, P < 0.01). Concentrations of both DHEAS and SHBG remained nearly unchanged. In conclusion, it was shown that a decline of ovarian hypertestosteronaemia was achieved in association with a flattening of the postprandial glucose and insulin increase by long-term treatment with acarbose. Side effects were limited to abdominal distension and flatulence and were absent using a low dosage of 50 mg acarbose/ meal (3 x 50 mg/day).

Acarbose↗
PubMed1996

CYCLIC adenosine 3',5'-monophosphate potentiates Ca2+ signaling and insulin secretion by phospholipase C-linked hormones in HIT cells.

Neurotransmitters and hormones, by binding to receptors linked to adenylate cyclase or phospholipase C (PLC), increase cytosolic free Ca2+ and potentiate glucose-induced insulin release from beta-cells. Interactions between both signaling pathways may occur and be of relevance to the regulation of insulin secretion. We demonstrate here that in single insulin-secreting HIT cells, forskolin and 8-bromo-cAMP, which stimulate Ca2+ influx through voltage-dependent Ca2+ channels (VDCC), cause a marked increase in the frequency, amplitude, and duration of Ca2+ transients evoked by hormones linked to PLC, such as arginine vasopressin (AVP) or bombesin. Forskolin also potentiates AVP- or bombesin-induced insulin secretion from populations of HIT cells in the presence of elevated glucose (10 mM). BAY K 8644, an activator of VDCC, mimicked the effects of elevated cAMP on both AVP- and bombesin-induced Ca2+ transients and insulin release, which suggests that enhanced Ca2+ influx through VDCC activated by cAMP-dependent mechanisms underlies the positive interactions of both signaling pathways on Ca2+ signaling and insulin secretion. Physiologically, synergistic cross-signaling between the cAMP- and Ca2+ -phosphoinositide signaling pathway could be important for the regulation of insulin release under conditions where extracellular glucose is high and beta-cells are exposed to multiple stimuli activating adenylate cyclase or PLC at the same time.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Circadian growth hormone secretion in asymptomatic human immune deficiency virus infection and acquired immunodeficiency syndrome.

Although anabolic effects of GH supplementation have been reported in acquired immune deficiency syndrome (AIDS) patients, the effects of human immunodeficiency virus (HIV) infection per se on GH secretion are unknown. Therefore, we evaluated the characteristics of GH secretion in eight asymptomatic HIV-infected men, eight clinically stable male AIDS patients, and eight healthy controls. Wasting AIDS patients were not included to circumvent the confounding effects of opportunistic disease on GH secretion. Samples for GH analysis were taken at 10-min intervals over 24 h. GH was measured by immunoradiometric assay (detection limit, 0.08 mU/L). Insulin-like growth factor I (IGF-I) and IGF-binding protein-3 were measured every 6 h. The pulsatile secretion of GH was evaluated by Cluster and DESADE analyses. No differences in number of peaks, peak amplitude, peak length, peak interval, or GH secretion per 24 h were found among the studied groups. IGF-I and IGF-binding protein-3 concentrations were not different among groups. Circadian GH secretion in asymptomatic HIV infection and AIDS without wasting is not different from that in healthy subjects. Therefore, anabolic effects documented in clinical trials with recombinant human GH in AIDS patients are not merely explained by alterations in the GH/IGF-I axis induced by HIV infection per se.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Serum leptin and weight reduction in female obesity.

Leptin, an adipocyte-derived hormone, induces a decrease in food intake and increases energy expenditure via hypothalamic interactions. In animal models obesity can be caused by leptin deficiency or by a dysfunction of the hypothalamic leptin receptor. Using a radioimmunoassay for the determination of leptin in human serum, we measured serum leptin levels in 227 otherwise healthy normal weight (N = 78; body mass index = 16.1-27.7 kg/m2) or obese women (N = 149; body mass index = 27.8-56.7 kg/m2). Fifty-three subjects were followed over a period of 12 weeks under weight reduction (800 kcal/day) and a subgroup of 33 for another 13 weeks after termination of the diet. Body mass index and serum leptin concentrations were measured longitudinally and compared to female controls not under diet. Under baseline conditions, log serum leptin levels were positively related to body mass index with a best fit using a non-linear regression (p < 0.001), indicating an attenuated increase in serum leptin levels with high body mass index. No subgroup with low serum leptin levels could be identified. Weight reduction induced a rapid decrease in serum leptin levels within the first 3 weeks to levels significantly lower than in body mass index-matched controls under normal diet (p < 0.001). This pattern was consistent after 6 and 12 weeks. Serum leptin levels increased again after the end of the diet but remained significantly lower than in the controls despite unrestricted calorie intake over 7 weeks. The rapid and persistent decrease in serum leptin to lower levels than expected from matched controls may explain the pertinent difficulties of obese subjects to cope with weight reduction.

Adult↗
PubMed1995

Extracellular ATP and UTP increase cytosolic free calcium by activating a common P2u-receptor in single human thyrocytes.

In single human thyrocytes extracellular ATP, ATP-gamma-S, ADP and UTP caused a concentration-dependent biphasic increase in [Ca2+]i. Consistent with a P2u-receptor the rank-order of potency was ATP = UTP > ATP-gamma-S > ADP, and cross-desensitization of the Ca2+ responses occurred between ATP and UTP. The initial transient peak in [Ca2+]i was resistant to extracellular Ca2+ depletion which demonstrates mobilisation of internal Ca2+ by IP3 whose formation was rapidly enhanced by ATP and UTP. By contrast, the sustained plateau phase required influx of external Ca2+. Ca2+ influx occurs most likely through a capacitative Ca2+ entry mechanism, which was shown to exist in these cells by experiments performed with thapsigargin. Thus, low micromolar concentrations of extracellular ATP and UTP activate a common P2u-receptor coupled to the C(a2+)-phosphatidylinositol signalling cascade in human thyrocytes. This indicates that extracellular nucleotides from various sources might play an important role in human thyroid physiology.

Adenosine Triphosphate↗
PubMed1995

Cognitive functioning in experimental hypoglycaemia assessed with event-related potentials.

Cognitive effects of experimentally induced hypoglycaemia were investigated by event-related brain potentials (ERPs) in auditory and visual classification tasks. In a cross-over design eight healthy male subjects (age 22-27 years) were studied under control conditions or following administration of 0.15 IU insulin kg-1. The ERPs showed preserved early cortical components, while the N2 component was greatly reduced in both modalities. P3 components did not show an influence of hypoglycemia. These results suggest that the cognitive deficits are due to an impairment of automatic feature extraction from the stimuli.

Adult↗
PubMed1995

Vasopressin induces frequency-modulated repetitive calcium transients in single insulin-secreting hit cells.

Ca2+ is central to the stimulation of insulin secretion from pancreatic beta-cells. Arginine-vasopressin (AVP) may participate in the modulation of insulin release. In the present study, the AVP-induced changes in cytosolic free Ca2+ ([Ca2+]i) were investigated in single fura-2 loaded insulin-secreting HIT cells. Stimulation with AVP (0.1-5 nM) caused repetitive Ca2+ transients. The frequency but not the amplitude of the Ca2+ transients was modulated by the concentration of AVP. High concentrations of AVP (10-100 nM) triggered a biphasic rise in [Ca2+]i. In Ca(2+)-free medium AVP caused only one or two Ca2+ transients. Withdrawal of extracellular Ca2+ rapidly abolished the AVP-induced Ca2+ transients in all cells tested. The Ca2+ channel blocker, verapamil (50 microM), reduced amplitude and frequency of the Ca2+ transients by about 25% and 60%, respectively, and terminated the Ca2+ transients in 2 of 6 cells. When HIT cells were incubated in Ca(2+)-free medium, and extracellular Ca2+ was restored, there was a small increase in [Ca2+]i. If, however, the agonist-sensitive Ca2+ pool was functionally depleted by repetitive stimulation with high concentrations of AVP or thapsigargin in Ca(2+)-free medium before extracellular Ca2+ was restored, an agonist-independent increase in [Ca2+]i was observed, which was transiently larger than in the control cells, and was mainly preserved in the presence of verapamil. Thus, depletion of the agonist-sensitive Ca2+ pool enhances the influx of extracellular Ca2+ through a Ca2+ entry mechanism independent from verapamil-sensitive voltage-dependent Ca2+ channels (VDCC).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Pulsatile growth hormone secretion in normal-weight and obese men: differential metabolic regulation during energy restriction.

Metabolic changes such as obesity and fasting modulate pulsatile growth hormone (GH) release in man, but the underlying mechanisms are still elusive. We studied the temporal pattern of pulsatile GH release in five normal-weight men (mean +/- SD: age, 29.8 +/- 4.9 years; body mass index [BMI], 24.3 +/- 1.8 kg/m2) and five obese men (age, 27.8 +/- 4.8 years; BMI, 38.9 +/- 4.8 kg/m2) during their regular energy consumption and the last 24 hours of a 96-hour fasting period. GH plasma levels were determined at 10-minute intervals and glucose level was measured every 20 minutes. GH pulse analysis was performed with three different algorithms. Insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding proteins (IGFBP-1, -2, and -3), and IGF-binding capacity (IGF-BC) were evaluated in samples collected at 7:00 AM, 3:00 PM, and 11:00 PM. Twenty-four-hour mean GH was basally higher in normal subjects (1.1 +/- 0.6 mU/L) than in overweight subjects (0.4 +/- 0.2, P < .01 v normal). The significant fasting-induced GH increase in normal-weight men (to 5.6 +/- 2.2 mU/L, P < .05 v basal) was inversely related to BMI (r = -.86, P = .0006). GH pulse amplitudes but not frequencies were different for both groups and were increased by fasting in normal subjects but not in obese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Effects of continuous and pulsatile administration of pituitary rat thyrotropin and recombinant human thyrotropin in a chronically cannulated rat.

Pulsatile secretion of thyrotropin (TSH) is a well characterized phenomenon in the human, yet only limited data are available from animal studies. We propose a combined model of chronic catheterization and suppression of endogenous TSH release in the rat allowing us to apply quantified pulses of different preparations of thyrotropin intravenously with minimal interference with endogenously produced hormone. Sprague-Dawley rats treated with drinking water containing 3,5,3'-triiodothyronine (T3) showed a significant 6-fold decrease of the rat TSH (rTSH) level after four days. Free thyroxine (FT4) levels were 9-fold below unsuppressed levels; FT4 response to exogenous TSH application above this suppressed baseline level was selected as an endpoint. Infusion studies compared pulsatile with continuous TSH administration. A low and a high dose of rTSH and recombinant human TSH (rec-hTSH) were administered. Levels of FT4 were compared after two and four days and responsiveness to a standard high bolus of rTSH 6 h after end of infusion was assessed. With regard to its potency for FT4 release, differences indicating a general trend as to superior efficiency of pulsatile TSH stimulation of the thyroid gland in comparison to continuous stimulation could be observed in all four experiments. More pronounced effects were seen after 2 and 4 days of high rTSH infusion and after 4 days of low rec-hTSH infusion. Comparison of FT4 responses to rTSH boli showed a 2- and 6-fold higher response in the pulsatile group compared to the continuous group after low and high rTSH infusion, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗