bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ghrelin-induced growth hormone secretion in humans
Authors: Peino R , Baldelli R , Rodriguez-Garcia J , Rodriguez-Segade S , Kojima M , Kangawa K , Arvat E , Ghigo E , Dieguez C , Casanueva F F 
Published: January 2005

Abstract
Ghrelin is a novel growth hormone (GH) releaser acylated peptide that has recently been purified from stomach, and which potently binds to the GH secretagogue receptor. Ghrelin releases GH in vitro and in vivo in animal models, however its actions, potency and specificity in humans are unknown. In the present study, 12 healthy subjects were studied: 6 underwent four tests with ghrelin administered i.v. at the dose of 0 (placebo), 0.25, 0.5 and 1 microg/kg which corresponds to 0, 18, 37 and 75 microg total dose. A further 6 volunteers underwent two tests on different days with ghrelin at the dose of 3.3 or 6.6 microg/kg which corresponds to 250 microg and 500 microg total dose. Ghrelin-mediated GH secretion showed a dose-response curve, in which 1 microg/kg was the minimally effective dose in some individuals, but not as a group. On the contrary, the total doses of 250 microg and 500 microg elicited a powerful GH secretion, with a mean peak of 69.8+/-9.2 microg/l and 90.9+/-16.9 microg/l respectively, and areas under the curve of 4435+/-608 and 6125+/-1008 microg/l per 120 min respectively. All of them statistically significant vs placebo and vs the 1 microg/kg dose. Ghrelin administration also elicited a relevant dose-response mediated prolactin secretion suggesting no specificity of its actions. No relevant side effects were observed with ghrelin apart from a hyperhydrosis episode in two individuals tested with the higher ghrelin doses. In conclusion, ghrelin is a potent releaser of GH in normal individuals, with a dose-response pattern of operation. No saturating dose was observed.
Mechanism of inhibition of cytochrome P450 C21 enzyme activity by autoantibodies from patients with Addison’s disease
Authors: Nikfarjam L , Kominami S , Yamazaki T , Chen S , Hewer R , Dal Pra C , Nakamatsu T , Betterle C , Zanchetta R , Rees Smith B , Furmaniak J 
Published: January 2005

Objective: To study possible mechanisms for the inhibition of cytochrome P450 C21 (steroid 21-hydroxylase) enzyme activity by P450 C21 autoantibodies (Abs)in vitro.Design: Two possible mechanisms for the inhibition of P450 C21 enzyme activity by P450 C21 Abs were studied: (a) conformational changes in the P450 C21 molecule induced by Ab binding and (b) the effects of Ab binding to P450 C21 on the electron transfer from the nicotinamide adenine dinucleotide phosphate reduced (NADPH) cytochrome P450 reductase (CPR) to P450 C21.Methods: The effect of P450 C21 Ab binding on the conformation of recombinant P450 C21 in yeast microsomes was studied using an analysis of the dithionite-reduced CO difference spectra. The effect of P450 C21 Abs on electron transfer was assessed by analysis of reduction of P450 C21 in the microsomes in the presence of CO after addition of NADPH.Results: Our studies confirmed the inhibiting effect of P450 C21 Abs on P450 C21 enzyme activity. Binding of the Abs did not induce significant change in the P450 C21 peak at 450 nm (native form) and did not produce a detectable peak at 420 nm (denatured form) in the dithionite-reduced CO difference spectra. This indicated that conformation of P450 C21 around the heme was not altered compared with the native structure. However, incubation of the P450 C21 in yeast microsomes with P450 C21 Ab inhibited the fast phase electron transfer from the CPR to P450 C21.Conclusions: Our observations suggested that the mechanism by which P450 C21 Abs inhibit P450 C21 enzyme activity most likely involves inhibition of the interaction between the CPR and P450 C21.
Defective lymphocyte caspase-3 expression in type 1 diabetes mellitus
Authors: Vendrame Francesco , Santangelo Carmela , Misasi Roberta , Dionisi Sabrina , Gizzi Chiara , Realacci Massimo , Grassetti Daniele , Di Mario Umberto , Dotta Francesco 
Published: January 2005

Objective: Activation-induced cell death (AICD) is a major mechanism in the regulation of peripheral tolerance and its impairment can determine the development of autoimmunity. In the present study, in order to evaluate the role of caspase-3 in type 1 diabetes mellitus (T1DM) AICD, caspase-3 expression was analyzed in peripheral blood lymphocytes from 37 new onset T1DM patients and from 36 normal control subjects (NC) in resting conditions and after anti-Fas-triggered apoptosis.
Methods: Caspase-3 expression was determined by semiquantitative RT-PCR and Western blot. Apoptosis was induced in activated lymphocytes by anti-Fas monoclonal antibody and quantified by flow cytometry and morphological analysis.
Results: Caspase-3 mRNA expression was reduced in resting lymphocytes in 18/37 T1DM patients and in 1/36 NC (P < 0.01). Patients studied for both Fas-mediated AICD and caspase-3 mRNA expression revealed that a reduced caspase-3 mRNA expression in resting lymphocytes occurred in all patients showing resistance to Fas-mediated apoptosis (T1DM vs NC, P < 0.02) with the exception of 3 patients who exhibited normal caspase-3 expression levels. Caspase-3 protein analysis confirmed mRNA data and showed an impaired expression of caspase-3 active form in T1DM subjects compared with NC.
Conclusions: Our data show that defective expression and function of caspase-3 in peripheral lymphocytes of T1DM patients may contribute to the development of AICD resistance in type 1 diabetes.
Regulation of H2O2 generation in thyroid cells does not involve Rac1 activation
Authors: Fortemaison N , Miot F , Dumont J E , Dremier S 
Published: January 2005

Objectives: The H2O2generating system of the thyrocyte and the O2−generating system of macrophages and leukocytes present numerous functional analogies. The main constituent enzymes belong to the NADPH oxidase (NOX) family (Duox/ThOX for the thyroid and NOX2/gp91phoxfor the leukocytes and macrophages), and in both cell types, H2O2generation is activated by the intra-cellular generation of Ca2+and diacylglycerol signals. Nevertheless, although the controls involved in these two systems are similar, their mechanisms are different. The main factors controlling O2−production by NOX2 are the cytosolic proteins p67phoxand p47phox, and Rac, a small GTP-binding protein. We have previously reported that there is no expression of p67phoxand p47phoxin thyrocytes. Here, we investigated whether Rac1 is an actor in the thyroid H2O2-generating system.Design and methods: Ionomycin- and carbamylcholine-stimulated H2O2generation was measured in dog thyroid cells pretreated with theClostridium difficiletoxin B, which inhibits Rac proteins. Activation of Rac1 was measured in response to agents stimulating H2O2production, using the CRIB domain of PAK1 as a probe in a glutathione S-transferase (GST) pull-down assay.Results: Among the various agents inducing H2O2generation in dog thyrocytes, carbamylcholine is the only one which activates Rac1, whereas phorbol ester and calcium increase alone have no effect, and cAMP inactivates it. Moreover, whereas toxin B inhibits the stimulation of O2generation by phorbol ester in leukocytes, it does not inhibit H2O2generation induced by carbamylcholine and ionomycin in dog thyrocytes.Conclusions: Unlike in leukocytes, Rac proteins do not play a role in H2O2generation in thyroid cells. A different regulatory cascade for the control of H2O2generation remains to be defined.
Serum parathyroid hormone (PTH) levels in smokers and non-smokers. The fifth Tromsø study
Authors: Jorde R , Saleh F , Figenschau Y , Kamycheva E , Haug E , Sundsfjord J 
Published: January 2005

Objective: Smoking is associated with reduced bone density and calcium absorption, and reduced serum levels of vitamin D. A compensatory increase in serum parathyroid hormone (PTH) would therefore be expected as a result of an altered calcium balance. However, reports on PTH levels in smokers are conflicting. As serum PTH levels give important information on the calcium balance, the PTH levels in smokers are of interest.Subjects and methods: In the fifth Tromsø study, smoking status was recorded and serum PTH measured in 7896 subjects. Intakes of calcium and vitamin D were evaluated with a food-frequency questionnaire. In a follow-up study on 205 subjects, serum 25-hydroxyvitamin D, calcium absorption, and renal excretion of calcium were measured in addition.Results: The serum PTH levels were significantly lower in smokers than non-smokers (3.1±1.4 vs 3.6±1.9 pmol/l in males; 3.1±1.5 vs 3.6±1.8 pmol/l in females (P< 0.001) after correcting for confounding variables, linear regression). In the smokers, there was no association between number of cigarettes smoked and serum PTH. One year after quitting smoking, serum PTH levels were similar to those of people who had never smoked. The smokers had significantly lower intake of vitamin D, lower serum levels of 25-hydroxyvitamin D and lower calcium absorption. The intake of calcium and the renal excretion of calcium were similar to that in non-smokers.Conclusions: Smokers have lower serum PTH levels than non-smokers. This cannot be explained by the predictors of serum PTH measured in our study.
Influencing the between-feeding and endocrine responses of plasma ghrelin in healthy dogs
Authors: Yokoyama Masayuki , Nakahara Keiko , Kojima Masayasu , Hosoda Hiroshi , Kangawa Kenji , Murakami Noboru 
Published: January 2005

Objectives: Ghrelin has recently been isolated from rat and human stomach as an endogenous ligand for the growth hormone (GH) secretagog receptor. Using beagle dogs, we investigated the distribution of ghrelin in the stomach and its possible role.
Methods: We examined: (i) GH release in response to ghrelin injection (0.5 or 5 μg/kg, i.v.), (ii) gastric localization of ghrelin-immunostained cells, (iii) changes in daily food consumption after ghrelin injection (3, 10, and 20 μg/kg, i.v.), (iv) plasma ghrelin levels under regular, but restricted feeding conditions, and (v) variations in plasma ghrelin levels in relatively lean, normal and obese dogs.
Results: Administration of ghrelin to dogs promptly increased circulating GH concentrations, although this effect was transitory and was maintained for only 20 min. Ghrelin was localized in the stomach fundus and body, but none was detected in either the pylorus or cardia. Administration of ghrelin at a dose of 20 μg/kg increased the daily food intake of beagle dogs. Plasma ghrelin levels peaked just before meal times, and then returned to basal levels. Obese dogs had higher plasma ghrelin levels than did normal and lean dogs.
Conclusions: These results indicate that ghrelin is a potent GH secretagog in dogs. The distribution of ghrelin-immunoreactive cells in the canine stomach resembles that of both the murine and human stomach. Ghrelin participates in the control of feeding behavior and energy homeostasis in dogs and may, therefore, be involved in the development of obesity.
Prognostic significance of successful ablation with radioiodine of differentiated thyroid cancer patients
Authors: Verburg Frederik A , de Keizer Bart , Lips Cornelis J M , Zelissen Pierre M J , de Klerk John M H 
Published: January 2005

Objectives: Currently, little is known about the prognostic significance of achieving successful ablation with the first dosage of I-131 in patients with differentiated thyroid cancer. This study aimed to assess the following: (i) whether successful or unsuccessful ablation at post-ablation follow-up has prognostic consequences; (ii) possible factors predicting success of ablation in a patient.
Methods: In order to do this, we retrospectively studied 180 patients with a median follow-up of 55 months. Ablation was considered to be successful if 1 year after the initial dosage of I-131 patients fulfilled all of the following criteria: not dead from thyroid cancer, no additional therapy needed for any kind for thyroid cancer within the first year, undetectable thyroglobulin (Tg) levels under TSH stimulation, and negative I-131 scintigraphy. Tg levels at the time of ablation (P < .001), lymph node metastasis (P = 0.04) and distant metastasis (P < .001) have a significant influence on the success of ablation. P values were calculated by Mann–Whitney U test and Chi-square test, respectively.
Results: Patients with successful ablation had a better prognosis than those with unsuccessful ablation: disease-free survival was 87% versus 49% after 10 years; additionally, thyroid-cancer related survival was 93% versus 78%.
Conclusion: We conclude that the extent of the remaining normal or neoplastic thyroid tissue influences the outcome of ablation, and that successful ablation leads to a better prognosis. It seems that it is very important to achieve complete ablation as soon as possible in order to ensure the best possible prognosis for a patient.
Long-term maintenance of the anabolic effects of GH on the skeleton in successfully treated patients with acromegaly
Authors: Biermasz Nienke R , Hamdy Neveen A T , Pereira Alberto M , Romijn Johannes A , Roelfsema Ferdinand 
Published: January 2005

Introduction: The anabolic actions of growth hormone (GH) are well documented. In acromegaly, the skeletal effects of chronic GH excess have been mainly addressed by evaluating bone mineral density (BMD). Most data were obtained in patients with active acromegaly, and apparently high or normal BMD was observed in the absence of hypogonadism. Data on BMD are not available after successful treatment of acromegaly. Whether the positive effect of GH excess on bone mass is maintained in the long term after clinical and biochemical cure of acromegaly remains to be established.
Patients and methods: In a cross-sectional study design, lumbar spine and femoral neck BMD was measured in 79 acromegalic patients cured or well controlled on octreotide treatment (45 male and 34 female patients; mean age 57±1 years). Successful treatment (by surgery, radiotherapy and/or use of octreotide) was defined as normal age-adjusted IGF-I. Mean time after biochemical remission was 10.2±7 years.
Results: Normal or increased BMD was observed at the femoral neck and lumbar spine in both men and women in remission after treatment for acromegaly. Similar results were obtained in patients in remission for 5 years or longer. Osteoporosis was present in 15% of the patients, with similar prevalence in men and women. There was no relationship between BMD and duration or severity of GH excess before treatment, gonadal status and presence of pituitary hormone deficiencies. Pituitary irradiation was a strong negative predictor of bone mass at the femoral neck. Long-term bone loss was observed only at the femoral neck.
Conclusion: Our data suggest that the anabolic effect of GH on trabecular and cortical bone remains demonstrable after remission of acromegaly, although it may not be maintained at cortical sites in the long term. In the present study, the lack of effect of gonadal status on BMD may be explained by the presence of only mild hypogonadism and by our policy of prompt hormonal replacement therapy for severe hypogonadism. The negative effect of pituitary irradiation on femoral neck BMD remains intriguing, although it is probably related to some degree of the diminished GH secretion frequently observed after this form of treatment.
Disease activity in acromegaly may be assessed 6 weeks after discontinuation of pegvisomant
Authors: Drake W M , Loureiro R A , Parkinson C , Monson J P , Besser G M , Trainer P J 
Published: January 2005

Objective: Pegvisomant, a modified growth hormone (GH) molecule, is a novel medical therapy for acromegaly that functions as a GH receptor antagonist. Serum GH cannot be used as a marker of disease activity in patients taking this form of therapy, partly because GH levels rise on pegvisomant and partly because the drug cross-reacts with many routine GH assays. The purpose of this study was to assess the time for which it is necessary to discontinue pegvisomant prior to biochemical reassessment of acromegaly.
Design and methods: This was a retrospective study of 13 patients (seven male, median age 61 years, range 43–77) enrolled in two separate, open-label studies of the efficacy and tolerability of pegvisomant in the treatment of acromegaly. All had been taking a stable dose of pegvisomant (median dose 15 mg daily, range 10–30) as monotherapy for at least 3 months before discontinuing the drug. After discontinuation of pegvisomant, serum IGF-I was measured at 0, 2, 4, 6 and 8 weeks in all patients. Serum GH (single sample) was measured in nine patients at 2, 4, 6 and 8 weeks, but not at baseline on account of the cross-reactivity of pegvisomant with the GH assay.
Results: Mean serum IGF-I rose from 210±105 ng/ml (s.d.) at baseline to 392±175 ng/ml at 2 weeks after discontinuation of pegvisomant (P < 0.0001). Although there was no statistically significant change in mean serum IGF-I beyond 2 weeks (412±181, 392±152 and 399±150 ng/ml at 4, 6 and 8 weeks respectively; P = 0.13 (2 vs 4 weeks), 0.31 (4 vs 6 weeks) and 0.46 (6 vs 8 weeks), serum IGF-I rose by more than twice the interassay coefficient of variation (CV) in two of the 13 patients between weeks 2 and 4. The standard deviation of the difference in serum IGF-I between time points was calculated. The values declined from 118% (weeks 0–2) 17%, 19.7% and 10% (weeks 2–4, 4–6 and 6–8 respectively). The expected measure if there was no systematic change in base would be 15% (1.4 ×interassay CV). Mean serum GH was virtually unchanged at 2–8 weeks after cessation of pegvisomant therapy.
Conclusions: These results suggest that the activity of acromegaly may be assessed by serum IGF-I levels 6 weeks after the discontinuation of pegvisomant.
C-peptide increases the expression of vasopressin-activated calcium-mobilizing receptor gene through a G protein-dependent pathway
Authors: Maestroni Anna , Ruggieri Dora , Dell’Antonio Giacomo , Luzi Livio , Zerbini Gianpaolo 
Published: January 2005

Objective: Although an increasing number of reports suggest that physiological concentrations of C-peptide protect against the development of diabetic nephropathy, possibly through the modulation of Na–K pump activity, the intracellular pathways controlled by C-peptide are still unrecognized. C-peptide and vasopressin share similar intracellular effects including the activation of calcium influx and endothelial nitric oxide synthase. Both hormones stimulate also the activity of Na–K pump activity. Whether the activity of C-peptide is mediated by the recently identified vasopressin-activated calcium-mobilizing receptor (VACM-1) has never been previously investigated.Design and methods: To clarify this issue, we evaluated the effect of C-peptide on VACM-1 RNA (measured by semiquantitative RT-PCR) and protein expression (measured by immunoblotting) in human skin fibroblasts (where a specific binding of C-peptide was demonstrated) and in human mesangial cells, the cellular target of diabetic nephropathy.Results: C-peptide-induced activation of VACM-1 was demonstrated in fibroblasts from six healthy individuals (0.51±0.1 vs 1.48±0.4, arbitrary units±s.e.,P= 0.025). This finding was paralleled by an increased VACM-1 protein expression (5.64±1.0 vs 8.47±1.2, arbitrary units±s.e.,P= 0.043). Similar results were confirmed in three independent cultures of human mesangial cells. VACM-1 activation in fibroblasts was insensitive to phosphatidylinositol-3-kinase inhibitor LY294002, but was inhibited by pertussis toxin, suggesting that activation of VACM-1 could be mediated by a G protein-coupled receptor.Conclusions: This study demonstrates for the first time that C-peptide activates VACM-1, possibly through a G protein-coupled receptor. Further studies are needed to clarify whether VACM-1 is involved in the protective effect of C-peptide against the development of diabetic nephropathy.
Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs
Authors: Petrossians Patrick , Borges-Martins Liliane , Espinoza Consuelo , Daly Adrian , Betea Daniela , Valdes-Socin Hernan , Stevenaert Achille , Chanson Philippe , Beckers Albert 
Published: January 2005

Introduction:Invasive GH-secreting pituitary adenomas are rarely cured by surgery and although long-term therapy with somatostatin analogs (SSAs) may be employed, hormonal control is achieved in only 60% of cases. The impact of tumor debulking on subsequent control of acromegaly with SSAs has not been studied previously.Methods:We studied retrospectively the response to SSA therapy in acromegalic patients before and after incomplete surgical tumor excision. A case review identified 24 acromegalic patients who had received SSA therapy for ≥1 month before and after gross total resection or debulking of adenomas. No patient received radiotherapy or combination treatment with SSAs and dopamine agonists during the study. GH and IGF-I responses to SSAs were recorded pre- and postoperatively. Postoperative SSA therapy was begun after a washout period of 1–3 months to assess the hormonal effects of the surgery alone.Results:Before preoperative SSA treatment, 24/24 (100%) patients had elevated GH levels and IGF-I levels were elevated in 19/21 (90.5%) patients with recorded values. During preoperative SSA treatment, GH and IGF-I levels were normalized in 7/24 (29.2%) and 11/24 (45.8%) patients respectively. Following postoperative washout, GH was controlled in only 3/24 (12.5%) patients, while IGF-I was controlled in 8/19 (42.1%) patients with available data. During the second SSA treatment period, normal GH levels were seen in 13/24 (54.2%) patients, while IGF-I control was noted in 18/23 (78.3%).Conclusion:Gross total tumor resection or debulking increases the likelihood of achieving biochemical disease control with SSAs in acromegalic patients with adenomas that were not amenable to complete surgical resection and in whom primary SSA therapy was unable to achieve good biochemical control.
Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas
Authors: van Houtum W H , Corssmit E P M , Douwes Dekker P B , Jansen J C , van der Mey A G L , Bröcker-Vriends A H J T , Taschner P E M , Losekoot M , Frölich M , Stokkel M P M , Cornelisse C J , Romijn J A 
Published: January 2005

Objective: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas.Methods: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a provenSDHDgene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done.Results: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catechol-amine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-typeSDHDallele in all cases.Conclusions: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.