bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of nuclear DNA pattern and its relationship with cell cycle activity parameters in multinodular goitre
Authors: Francia Giuseppe , Azzolina Luigi , Mantovani Toscana , Vittoria Daví Maria , Brazzarola Paolo , Valerio Adriano , Petronio Renato , Sussi Pierluigi 
Published: November 2003

OBJECTIVERecent studies suggest that the malignancy rate in multinodular goitre is not significantly different from that observed in solitary nodules and that chromosomal aberrations are not infrequent in multinodular goitre. To further investigate this topic we determined the DNA pattern in multinodular goitres.DESIGN DNAploidy and cell cycle activity parameters were determined in multinodular goitres.PATIENTSWe evaluated 235 patients (185 female, 50 male, mean age 52 ± 13 years), who had undergone thyroidectomy; 11 of them harboured occult differentiated microcarcinoma.MEASUREMENTS DNAindex (DI), coefficient of variation of G0/G1 phase (CV), percentage of cells in S phase (%S) and in G2 + M phase (%G2‐M) and proliferative index (PI = %S + %G2‐M) were determined by flow cytometric analysis (FCM) in tissue samples taken from 3 different areas of the thyroid gland.RESULTSAneuploid DNA was found in 50 goitres without carcinoma (22.3%) and in 5 goitres with carcinoma (45.5%). The mean PI of euploid cells in the goitre without carcinoma was significantly higher in the goitres with an aneuploid component compared to the goitres without aneuploidy (10.8 ± 1.3 SEM vs 6 ± 0.32; P ± 0.001). Also, the percentage difference between maximal and minimal PI found within each goitre (δPI %) was higher in the former group (373 ± 49 SEM vs 142 ± 11.3; P < 0.0001). The PI was significantly higher in goitres with carcinoma compared to the goitres without carcinoma (12.9 ± 3.2 SEM vs 7.07 ± 0.40; P < 0.05).CONCLUSIONSThe finding of increased proliferation rate in goitres with an aneuploid or neoplastic component suggests that some factors involved in goitrogenesis could also be responsible for the development of chromosomal aberrations and/or for the selection of cellular clones endowed with high growth potential.
Post‐menopausal and chronological age have divergent effects on pituitary and hypothalamic function in episodic gonadotrophin secretion
Authors: Lambalk C. B. , De Boer L. , Schoute E. , Popp‐Snyders C. , Schoemaker J. 
Published: November 2003

OBJECTIVE Ageing is known to reduce gonadotrophin secretion in post‐menopausal women. To what extent the hypothalamus and pituitary are involved in this process is not clear. The aim of this study was to compare pulse characteristics of FSH and LH in relation to chronological and post‐menopausal age. Based on the gonadotrophin response to GnRH, we assessed the extent to which pituitary and/or hypothalamic ageing is responsible for the observed changes.DESIGN Blood samples were obtained from post‐menopausal women every 10 minutes for 6 hours. Subsequently, 100 μg GnRH was administered intravenously and blood samples taken after 30, 60 and 90 minutes.PATIENTS Twenty healthy women aged 47–72 years and between 1 and 30 years after the menopause.MEASUREMENTS Plasma LH and FSH were measured by immunoradiometric assay. Pulses were identified by a computerized pulse detection program. End points were the mean number and amplitude of pulses, the mean LH and FSH concentrations during the 6‐hour study period and the maximal LH and FSH increments following GnRH.RESULTS Mean LH and FSH levels did not change with chronological age but the LH pulse frequency declined significantly and the response to GnRH increased. Mean LH levels declined with post‐ menopausal age without alteration in LH pulse frequency but with a significant decrease in pituitary LH response to GnRH. FSH levels remained unchanged.CONCLUSIONS Post‐menopausal ageing seems to have a major suppressive effect on pituitary gonadotroph function, while chronological ageing mainly affects the hypothalamic regulation of LH secretion.
Urinary IGF and IGF binding protein‐3 in children with disordered growth
Authors: Gill M. S. , Whatmore A. J. , Tillman V. , White A. , Addison G. M. , Price D. A. , Clayton P. E. 
Published: November 2003

OBJECTIVE Both IGF‐l and IGFBP‐3 reflect spontaneous GH secretion in healthy individuals. We have evaluated the clinical usefulness of urinary IGF‐I and IGFBP‐3 measurements in the diagnosis of children with disordered growth.DESIGN Serum IGF‐I and IGFBP‐3 radioimmunoassays (RIA) were developed, and modified for quantitation in urine. The relationship between serum and urine levels, and the performance of these tests in the diagnosis of GH deficiency (GHD) were examined.PATIENTS Sixty‐nine children (age 9.5±3.6 years; 37 boys, 32 girls) provided a timed overnight urine collection and a serum sample collected on the same morning. Subjects were defined as GHD (n=22) or short normal (SN; n=47) on the basis of medical history, clinical examination, auxology and peak response to a GH stimulation test (<20 mU/l in GHD patients).MEASUREMENTS IGF‐I and IGFBP‐3 in serum and urine were measured by RIA, urinary GH (uGH) by immunoradiometric assay (IRMA) after dialysis and urinary creatinine by the alkaline picrate method. Urine results were expressed as total amount excreted (tulGFBP‐3 (μg), tulGF‐I (ng), tuGH (ng), tuCrt (mmol).RESULTS Urine IGF‐I and IGFBP‐3 excretion correlated significantly to serum levels of IGF‐I and IGFBP‐3 and also to tuGH excretion. There was a strong positive relationship between both urinary peptides and tuCrt, which suggested that renal filtration was the source of these peptides in urine. In addition, there were significant correlations with age, bone age and height SD score, of similar magnitude to those for tuGH. In prepubertal children, serum IGF‐I and IGFBP‐3 were significantly lower in GHD compared with SN children, while in puberty only serum IGFBP‐3 was significantly lower in GHD. There was no difference, however, in tulGF‐I or tulGFBP‐3 between GHD and SN children either prepubertally or in puberty with near complete overlap of the values between groups.CONCLUSION SMeasurements of tulGF‐I and tulGFBP‐3 have no place in the diagnosis of childhood GHD. Nonetheless, the significant correlations between serum and urinary IGF‐I and IGFBP‐3 levels and their correlation to uGH indicate that these peptides could be used as non‐invasive physiological markers of the GH‐IGF axis.
Clinico‐pathological study of Cushing's disease with large pituitary adenoma
Authors: Ikeda H. , Yoshimoto T. , Ogawa Y. , Mizoi K. , Murakami O. 
Published: November 2003

OBJECTIVETo explore the biological and morphological differences between large Cushing's adenomas and small adenomas, we investigated the clinical, endocrinological, neuroradiological, and histological features of patients with large Cushing's adenomas and compared them with patients with small Cushing's adenomas.PATIENTSFive of 250 patients with Cushing's disease undergoing trans‐sphenoidal operations from 1989 to 1995 had large adenomas with maximum diameters greater than 30 mm. The clinical characteristics of these five patients were compared with the 14 patients with Cushing's disease with small adenomas in our series.RESULTSOedema, myopathy, and mental disturbance were more frequent and hypertension was less frequent among patients with large adenomas. The high‐dose (8 mg) dexamethasone test did not suppress cortisol production in any of the five patients. Invasion into surrounding tissue was demonstrated by magnetic resonance imaging in all five cases. All five large adenomas had scarce or no periodic acid‐Schiff‐positive granules and were sparsely granulated ultrastructurally. Three tumours contained cells with honeycomb Golgi apparatus which rarely contained immature secretory granules. One Crooke's cell adenoma contained trapped or displaced secretory granules. The other tumour had dilated trans‐Golgi network‐derived vacuoles that contained reticular or circular electron‐dense material. These findings were in striking contrast to those of small Cushing's adenomas, which showed strong PAS positivity, densely‐packed granulation, and had prominent Golgi complex harbouring developing secretory granules.CONCLUSIONSWe found that the tumour cells in large adenomas produced only small amounts of ACTH, and showed indications of disturbances in the regulated exocytotic pathways. These factors may account for the different clinical characteristics of Cushing's disease with large pituitary adenomas.
Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary‐adrenal activity
Authors: Korbonits Márta , Trainer Peter J. , Little John A. , Edwards Ray , Kopelman Peter G. , Besser G. Michael , Svec Frank , Grossman Ashley B. 
Published: November 2003

BACKGROUNDLeptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects.SUBJECTS AND DESIGNWe have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18–25) and in a group of 12 moderately‐severely obese subjects (BMI range 34–61). We also studied the effect of food and fastina in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion.RESULTSMean leptin levels were significantly higher in the obese than in the lean group (42.7 ± 3.41 vs 5.35 ± 1.55 μg/l, mean ± SEM; P<0.001), and showed a positive correlation with body mass index (r=+0.71; P<0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20‐hour fast in our subjects as a group (92 ± 0.03% of basal, P=0.03); however, in the lean subjects the fall was greater (88 ± 0.04% of basal, P=0.02) than in the obese, where it did not reach statistical significance (96 ± 0.05% of basal). Pre‐meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r=+0.65; P<0.001 and r=+0.78; P<0.001, respectively) in all subjects, while pre‐meal and peak serum cortisol levels showed an inverse relation with leptin levels (r=−0.53; P=0.002 and r=−0.41; P=0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long‐term insulin excess per se is associated with increased circulating leptin concentrations.CONCLUSIONSLeptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo‐pituitary‐adrenal axis: whether this is a direct influence of leptin on hypothalamo‐pituitary‐adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.
Components of biological variation, including seasonality, in blood concentrations of TSH, TT3, FT4, PRL, cortisol and testosterone in healthy volunteers
Authors: Maes M. , Mommen K. , Hendrickx D. , Peeters D. , D’Hondt P. , Ranjan R. , De Meyer F. , Scharpe S. 
Published: November 2003

OBJECTIVEThere are few detailed studies of annual or seasonal variations in hormone concentrations in man. This study examines the components of biological variation, including seasonality, in plasma TSH, total T3 (TT3), free T4 (FT4), PRL, cortisol and testosterone in healthy volunteers.DESIGNMonthly blood samplings for the assay of the above hormones were collected during one calendar year.SUBJECTSThirteen normal men and 13 normal women participated in the present study (mean age 38.7 ± 13.4 years).MEASUREMENTSAssays of TSH, TT3 and FT4 were carried out by means of Immunoradiometric assays (IRMA), PRL by ELISA, cortisol by a fluorescence immunoassay, and testosterone with RIA. The time series were analysed by means of (bivariate or multivariate) spectral and cosinor analyses.RESULTSSignificant annual, four‐monthly and biannual rhythms were detected in serum TSH; the lowest TSH values were observed in spring. A significant annual rhythm was detected in TT3, with lower values in spring and summer than in the other seasons. The peak–trough differences in the yearly variation expressed as a percentage of the mean were 29.1% and 8.2% for TSH and TT3, respectively. The yearly variation in plasma cortisol was significantly different between men and women: in men, 5.9% of the variation was explained by an annual rhythm, while in women 14.7% was explained by the fourth and seventh harmonical wave. The peak–trough differences in the yearly variation in plasma cortisol were 17.6% and 31.8% in men and women, respectively. There were no significant seasonal rhythms in PRL, FT4 or testosterone. The intraindividual/interindividual CV values were: TSH 29.3/48.4%, TT3 9.4/18.5%, FT4 7.1/9.1%, PRL 39.2/65.0%, cortisol 21.7/46.2%, and testosterone 12.6/40.8%.CONCLUSIONSThe degree of individuality measured in the plasma hormones is such that conventional population‐based reference ranges may not correctly identify major alterations in these hormones in individual subjects.
The c‐erbB‐2/neu proto‐oncogene in human pituitary tumours
Authors: Ezzat Shereen , Zheng Lei , Smyth Harley S. , Asa Sylvia L. 
Published: November 2003

OBJECTIVEThe aetiology of most pituitary tumours remains unknown. We have examined the potential role of the neu receptor proto‐oncogene in human pituitary tumorigenesis.MATERIALS AND METHODSTen non‐tumorous pituitary glands and 16 morphologically characterized functional and clinically non‐functioning pituitary adenomas were studied. Protein expression was examined by immunohistochemistry, mRNA expression by RT‐PCR and competitive PCR, gene amplification by differential PCR, and point mutations by DNA sequencing.RESULTSCytoplasmic positivity for neu was identified in a few scattered cells of the non‐tumorous adenohypophysis using an antibody to the intracytoplasmic domain of neu, but no membrane staining was found with an antibody to the extracellular domain; the latter is said to reflect gene amplification. mRNA transcript signals of the expected size were identified in the normal adenohypophysis and in all 16 adenomas examined. No increase in the degree of mRNA expression, however, was noted in the different tumour types compared to normal human pituitary tissue as determined by competitive PCR. As neu can be activated to an oncogene by a point mutation in the transmembrane region, nucleotide substitutions in this domain were investigated. Direct sequencing of codon 659 revealed no point mutations in any of the tumours. Furthermore, since amplification of neu has been noted in various human malignancies, DNA from these tumours was examined by differential PCR. No detectable differences were noted between the neu gene and the single‐copy reference gene IFN‐γ.CONCLUSIONThe neu gene is expressed in adenohypophysial cells and their tumours. In pituitary adenomas, this expression is not associated with gene amplification or activating mutations to suggest a direct role in pituitary tumorigenesis.
Growth deficiency in polytransfused β‐thalassaemia patients is not growth hormone dependent
Authors: Cavallo Luciano , Gurrado Raffaele , Gallo Francesco , Zecchino Clara , De Mattia Domenico , Tatò Luciano 
Published: November 2003

OBJECTIVEGrowth deficiency is commonly seen in polytransfused β‐thalassaemia patients, especially in adolescence. It is not completely dependent on the lack of their pubertal growth spurt. GH impairment at different levels (hypothalamic or pituitary) and/or a reduced IGF‐1 synthesis have been suggested the main causes of stunted growth in these patients. We evaluated the relationship between GH reserve and growth in short β‐thalassaemia patients.PATIENTSTwenty‐nine short patients (height <−1.8 SDS for chronological age) were divided into two groups (low and normal responders) on the basis of their GH peak during insulin and clonidine tests (≤ and > 20 mU/l, respectively). All but one low responders underwent the GHRH test to exclude the impairment of somatotroph function and in eight of them an IGF‐1 generation test was also performed. The two groups were compared with each other with respect to growth (height deficiency, height velocity, bone age and bone delay), haematological characteristics (serum ferritin levels, age at the start both of low (subcutaneous) s.c. infusion of desferrioxamine and of transfusional therapy) and serum IGF‐1 and IGF‐1 binding protein 3 levels.RESULTSThirteen patients (45%) (11 males, two females) were low responders, all but two having serum IGF‐1 < 5th centile (< 0.1 centile in 42%); the GHRH test excluded the impairment of somatotroph function in 8/12. Height deficiency, serum ferritin levels, and age at the start of s.c. chelating therapy did not differ in low compared to normal responders. Height was negatively correlated both with the age at the start of s.c. chelating therapy and with serum ferritin levels.CONCLUSIONThe reduction of GH reserve, more frequently due to a hypothalamic than to a pituitary dysfunction, is frequent in polytransfused β‐thalassaemia patients, especially in males. The height function is not related to the GH reserve, given the current methods for testing GH reserve. Late start of s.c. chelating therapy as well as haemosiderosis seem to play a role in the height deficiency, but not in GH reserve. Impairment of GH secretory reserve, therefore, cannot be considered the main cause of height deficiency in these patients.
Metyrapone pre‐treated inferior petrosal sinus sampling in the differential diagnosis of ACTH‐dependent Cushing's syndrome
Authors: Cuneo Ross C. , Lee Winnifred , Harper John , Mitchell Ken , Ward Greg , Leigh Atkinson R. , Salkield Ian , Cameron Donald P. 
Published: November 2003

BACKGROUNDInferior petrosal sinus sampling (IPSS) is a useful investigative technique in the differential diagnosis of ACTH‐dependent Cushing’s syndrome. Diagnostic accuracy is improved by the administration of corticotrophin releasing‐factor (CRF) during the procedure to stimulate ACTH secretion. We hypothesized that, given the unavailability of CRF in Australia, stimulation of ACTH secretion from tumorous corticotrophs with metyrapone treatment before IPSS may be useful.AIMSTo describe our clinical experience with a novel diagnostic test, and to compare results between IPSS with and without metyrapone pre‐treatment.SETTINGMetropolitan, Australian university teaching hospital.PATIENTS18 patients were studied on 21 occasions: three with Cushing’s disease without metyrapone treatment prior to IPSS (M−), 11 with Cushing’s disease with metyrapone pretreatment (M+), three with ectopic ACTH syndrome, and one with pseudo‐Cushing’s syndrome.TREATMENTPatients received oral metyrapone, median dose 750 mg 6 hourly, for 24 h before IPSS.RESULTSNo major side effects were noted. Metyrapone increased serum 11‐deoxycortisol concentration to a median of 400 nmol/l (range 36–1310) on the morning of the test. Radiological confirmation of correct catheter placement was shown in 36/42 inferior petrosal sinuses (86%). Median peak central : peripheral ACTH ratios were 9.8 for M− pituitary adenomas (range 5.7–13.6), 12.9 for the technically successful M+ pituitary adenomas (range 8–54.1), and 1.6 for M+ ectopic ACTH syndrome cases (range 1.2–3.4). Repeat studies in unoperated patients with ectopic ACTH syndrome showed ratios <1.6. IPSS showed median peak ACTH concentrations of 190 ng/l for M− pituitary adenomas (range 83–205), 595 ng/l for the technically successful M+ pituitary adenomas (range 80–7630; P = 0.035 compared to M−), and 62 ng/l for M+ ectopic ACTH syndrome cases (range 47–220). IPSS correctly identified the pituitary source of ACTH production in all cases of Cushing’s disease (except one technical failure where MRI revealed a lesion). MRI scanning correctly identified a lesion in 3/14 operated Cushing’s disease cases. IPSS correctly lateralized 1/3 M− and 7/8 M+ Cushing’s disease cases where the procedure was technically successful and surgical descriptions adequate. Pituitary exploration revealed a visible lesion in 75% of cases corresponding to the side predicted by IPSS; ‘blind’ hemi‐hypophysectomy was performed on the side predicted from IPSS in the remainder. All cases of Cushing’s disease were cured or improved following surgery, with a median follow‐up of 2.8 years (range 0.7–5.9).CONCLUSIONSMetyrapone pre‐treated inferior petrosal sinus sampling is safe, and appears to induce high ACTH output from pituitary corticotroph adenomas. The technique has allowed accurate localization and treatment of pituitary corticotroph microadenomas.
Expression of adrenocorticotrophic hormone receptor mRNA in human adrenocortical neoplasms: correlation with P450scc expression
Authors: Reincke Martin , Beuschlein Felix , Latronico Anna‐Claudia , Arlt Wiebke , Chrousos George P. , Allolio Bruno 
Published: November 2003

OBJECTIVEAdrenocorticotrophin (ACTH) is the main hormone‐regulating steroid secretion from the adrenal cortex. The ACTH receptor (ACTH‐R) has recently been cloned, allowing systematic evaluation of its expression and function in adrenal tumorigenesis. We investigated ACTH‐R and P450 side‐chain cleavage enzyme (P450scc) mRNA expression in a variety of neoplastic adrenocortical tissues by Northern blot and reverse‐transcriptase‐PCR (RT‐PCR).PATIENTS AND MEASUREMENTSWe studied tissue from eight normal adrenals, six diffuse adrenocortical hyperplasias in patients with ACTH‐dependent Cushing's syndrome, 22 adrenal adenomas, six carcinomas and two carcinoma cell lines. Poly A mRNA was electrophoresed, immobilized on a nylon membrane and hybridized using α32P‐CTP labelled human ACTH‐R and P450scc cDNAs.RESULTSMean ACTH‐R mRNA expression showed significant differences between groups (P=0.0001), but appeared to be independent of plasma ACTH concentrations. Compared to normal adrenal =100±12%), expression was low in non‐functional adenomas (23±11%) and carcinomas (19±12%), intermediate in adrenocortical hyperplasias (88±6%) and cortisol‐producing adenomas (81±15%) and high in aldosteronomas (175±29%). In adenomas, ACTH‐R mRNA expression correlated closely with the expression of P450scc mRNA r=0.8, P=0.0001) suggesting regulation by similar factors. However, carcinomas and cancer cell lines did not show a positive correlation between these two parameters r=−0.44, P=0.2).CONCLUSIONSWe have demonstrated that plasma ACTH is not the major factor influencing ACTH‐receptor mRNA expression in neoplastic adrenal tissue. In benign tumours of the adrenal cortex there was a close positive correlation between ACTH‐receptor mRNA and P450scc mRNA which was missing in adrenocortical carcinomas, probably as a result of tumour dedifferentiation.