bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations of the 11p15 imprinted region and the IGFs system in a case of recurrent non‐islet‐cell tumour hypoglycaemia (NICTH).
Authors: Bertherat Jérôme , Logié Armelle , Gicquel Christine , Mourriéras Florence , Luton Jean Pierre , Le Bouc Yves 
Published: March 2003

BACKGROUND AND OBJECTIVENon‐islet‐cell tumour hypoglycaemia (NICTH) is a rare disorder and has been explained by oversecretion of non mature IGF‐II and dysregulation of the IGFs sytem. The mechanisms responsible for tumoural IGF‐II overexpression in NICTH have been rarely studied. We report an extensive study of IGF‐II and IGFBPs as well as chromosome 11p15 gene expression regulation in a case of a pleural fibrosarcoma in a 63‐year‐old patient presenting with NICTH.METHODS AND RESULTSAbnormal high molecular weight precusor forms of IGF‐II were present in the patient's serum and were associated with dramatic alterations in the circulating levels of IGF‐I, IGF‐II and their binding proteins, as well as an inhibition of the somatotroph axis. These alterations returned to normal following complete surgical removal of the tumour. No structural change in chromosome 11p15 region was apparent in the tumour. However, dysregulation of this imprinted region was demonstrated, leading to the loss of imprinting of the IGF‐II gene associated with high IGF‐II expression, and by contrast decreased level of expression of H19 and p57KIP2 genes. Recurrence of the tumour four years latter was not associated with hypoglycaemia or changes in the levels of circulating IGFs or IGFBPs, despite IGF‐II overexpression by the tumour. This suggests that a large tumour volume is required to reach high enough levels to cause changes in the levels of circulating IGFs and IGFBPs, and to cause hypoglycaemia.CONCLUSIONThese results suggest that a dysregulation of gene expression and imprinting of chromosome 11p15 region is associated with tumour growth and IGF‐II overexpression in non‐islet‐cell tumour hypoglycaemia.
Inhibins A and B are regulated differentially in the early post‐partum period
Authors: Burger  , Mamers  , Groome  
Published: March 2003

BACKGROUNDThe early postpartum period is characterized endocrinologically by a rapid fall in the levels of oestradiol (E2) and immunoreactive inhibin, and a delayed rise in serum follicle stimulating hormone (FSH). No description is currently available of changes in serum inhibins A and B.OBJECTIVESThe present study aimed to examine the levels of inhibin A and B during the early weeks of postpartum lactational amenorrhoea, to determine whether there was evidence for differential regulation of the two hormones at a time when no dominant follicle was developing in the ovary.SUBJECTS AND METHODSSerum samples were available from 12 subjects aged 29–38 in whom postpartum levels of FSH, immunoreactive inhibin, E2 and prolactin had been examined previously. Samples for hormone assays had been obtained prior to delivery, daily for the 3–5 days postpartum, and weekly thereafter. Inhibins A and B were measured by specific ELISA assays, and results were calculated as 10 day averages for samples obtained on days 1–10, 11–20, 21–30, etc. postpartum. Normal hormone concentrations for reference were obtained from volunteers, also aged 29–38, sampled on days 3–5 of a normal menstrual cycle.RESULTSInhibin A in the predelivery sample ranged from 62 to 1243 ng/l, geometric mean 592. Concentrations fell rapidly postpartum and reached a nadir in the low follicular phase range between days 5 and 37 postdelivery, mean 13.6 days. The concentrations of both inhibin B and FSH rose 14–27 days postpartum from their initially low postdelivery levels, to reach the normal follicular phase range. These increases in concentration were significantly correlated in all individual subjects.CONCLUSIONSThe secretion of inhibin A and B is regulated differentially during the early stages of lactational amenorrhoea, just as it is in the late luteal phase of the normal menstrual cycle. Whilst inhibin A falls postpartum, reflecting cessation of placental function, and remains low until ovulatory cycles are resumed, FSH and inhibin B rise after a delay of two weeks or more. It is postulated that the rise of inhibin B is the result of secretion from a cohort of small follicles stimulated by rising FSH levels.
Plasma concentrations of tumor necrosis factor‐α (TNF‐α) and soluble TNF receptors in patients with bulimia nervosa
Authors: Nakai Yoshikatsu , Hamagaki Seiji , Takagi Ryuro , Taniguchi Ataru , Kurimoto Fumihiko 
Published: March 2003

BACKGROUNDTumor necrosis factor‐α (TNF‐α) is a cytokine with numerous immunological and metabolic activities. In addition, TNF‐α can stimulate a variety of physiological, neuroendocrine and behavioural responses of the central nervous system. In experimental animals, TNF‐α induces changes in physiological and behavioural parameters which have also been observed in eating disorders. The biological activities of TNF‐α are mediated by two structurally related, but functionally distinct receptors, TNF‐RI and TNF‐RII. Since injection of TNF‐α results in increased shedding of TNF‐α receptors, it is likely that TNF‐α release is reflected by soluble TNF‐receptors (sTNF‐Rs) levels.AIMSWe studied plasma concentrations of TNF‐α and two sTNF‐Rs (sTNF‐RI and sTNF‐RII) in female patients with bulimia nervosa.DESIGN AND PATIENTSTwenty female patients with bulimia nervosa (BN) and 20 age‐matched normal women (N) were studied.MEASUREMENTSPlasma TNF‐α concentrations were measured by enzyme immunoassay kit and plasma concentrations of sTNF‐RI and sTNF‐RII were measured by enzyme‐linked immunosorbent assay.RESULTSPlasma TNF‐α concentrations in BN were significantly higher than those in N (4.7 ± 0.5 ng/l vs. 1.6 ± 0.1 ng/l; P < 0.01). Although no significant difference was observed in plasma sTNF‐RI concentrations between the two groups, plasma sTNF‐RII concentrations in BN were significantly higher than those in N (2080.0 ± 107.5 ng/l vs. 1569.5 ± 84.0 ng/l; P < 0.01). Plasma TNF‐α concentrations were significantly related to plasma sTNF‐RI concentrations (r = 0.511, P < 0.05) and to plasma sTNF‐RII concentrations (r = 0.532, P < 0.05) in bulimic patients. However, plasma TNF‐α concentrations were not related to body fat mass or to bulimic behaviours in these patients.CONCLUSIONSOur present findings suggest that the adipose tissue may not be the immediate source of TNF‐α in bulimic patients but the increase in plasma TNF‐α in these patients may be derived from the central nervous system sources. The elevated sTNF‐RII may reflect different shedding kinetics compared with sTNF‐RI in bulimic patients.
Goitre prevalence and thyroid abnormalities at ultrasonography: a comparative epidemiological study in two regions with slightly different iodine status
Authors: Knudsen Nils , Bülow Inge , Jørgensen Torben , Laurberg Peter , Ovesen Lars , Perrild Hans 
Published: March 2003

OBJECTIVEThe association between severe iodine deficiency and endemic goitre is well established, but little information is available on the relation between milder degrees of iodine deficiency and goitre prevalence.SUBJECTSIn a comparative epidemiological study performed in two regions in Denmark, we examined 4649 subjects from the general population, women aged 18–65 years and men aged 60–65 years.METHODSUltrasonography and palpation of the thyroid was performed in all participants. Iodine excretion was measured in casual urine samples. Previous thyroid disease was detected by questionnaires, personal interviews and tracing of records.RESULTSThe median iodine excretion was 61 μg/l (mild iodine deficiency (ID)) and 45 μg/l (moderate ID) in the two regions. Median thyroid volume at ultrasonography was 11.9 ml (mild ID) and 13.6 ml (moderate ID), P < 0.001, and thyroid enlargement was found in 15.0% (mild ID) and 22.6% (moderate ID), P < 0.001. Goitre prevalence increased in both regions with age to the age group 40–45 years, but not after that age. Subjects who had moved from the moderate ID to the mild ID area had the same prevalence of thyroid enlargement as the subjects staying permanently in the mild ID area. Thyroid nodules at ultrasonography were found in 30% in both regions, but nodules were larger and more often palpable in the moderate ID area. Palpable goitre was found in 9.8% (mild ID) and 14.6% (moderate ID), P < 0.001. The greatest regional difference in thyroid abnormalities was found among men.CONCLUSIONMarked differences in the prevalence of thyroid abnormalities were found in these regions with modest differences in iodine excretion.
The diagnosis of growth hormone deficiency (GHD) in successfully treated acromegalic patients
Authors: Murray R. D. , Peacey S. R. , Rahim A. , Toogood A. A. , Thorner M. O. , Shalet S. M. 
Published: March 2003

Due to persistent qualitative abnormali‐ties in GH secretion following treatment, and lack of a sensitive marker of GHD in mid‐adult life it is extremely difficult to diagnose GHD in treated acromegalic patients. The diagnosis of GHD in patients with pituitary disease relies on provocative tests of GH reserve. Arginine releases GH by reducing somatostatin inhibition of GH release, whereas GH secretagogues (GHS) affect GH release by direct stimulation of the GHS receptor, though an intact GH releasing hormone (GHRH) axis is a prerequisite. The peak GH response to insulin‐induced hypoglycaemia and arginine in acromegalic patients, in whom basal serum GH levels of less than 5 mU/l have been achieved, is greatly diminished in those treated by hypothalamo–pituitary irradiation. We aimed to study the response of successfully treated acromegalic patients to the growth hormone secretagogue hexarelin in view of its different putative mechanism of action, and in addition, to determine whether it has any value in the diagnosis of GH deficiency in this subset of patients.Nineteen acromegalic patients, in whom mean serum GH levels below 5 mU/l have been achieved through treatment, were recruited. Eight of the patients had been treated by surgery alone (Group A) and 11 had received primary or postoperative irradiation (Group B).All patients underwent 20 min blood sampling to provide a 24‐h GH profile. Serum IGF‐I was measured from a sample drawn between 0900 h and 1000 h. On a second visit arginine 20 g/m2 was infused over 30 min, blood samples were taken before commencing the infusion and at 30‐min intervals thereafter for 180 min. At the final visit hexarelin 1·5 mcg/kg was administered as an intravenous bolus at t = 0. Blood was drawn at 15‐min intervals from − 30 to 180 min.All patients in group A showed an increment in serum GH following hexarelin (ΔGHHEX) > 20 mU/l, a normal response to arginine, and a mean 24‐h GH > 0·5 mU/l. In group B only 4/11 achieved a ΔGHHEX > 20 mU/l, 5/11 producing a response of < 2 mU/l. Four of the five patients with a ΔGHHEX < 2 mU/l were also demonstrated to have a mean 24‐h GH of < 0·5 mU/l and serum IGF‐I SDS < + 0·5. All four patients in Group B who achieved a ΔGHHEX > 20 mU/l, were observed to show an absent or minimal GH response to arginine.Despite loss of the GH response to arginine, the ΔGHHEX is retained in a proportion of those patients in whom ‘safe’ GH levels were achieved following irradiation. From the putative mechanisms of action of these provocative agents a plausible explanation would be that the GHRH axis is more resilient than endogenous somatostatin‐secreting neurones to radiation‐induced damage. Furthermore, GH secretagogues may have a role, in combination with serum IGF‐I levels, in the diagnosis of GH deficiency in treated acromegaly.
A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor gene
Authors: Söderlund D. , Canto P. , De La Chesnaye E. , Ulloa‐Aguirre A. , Méndez J. P. 
Published: March 2003

BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH‐R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH‐R gene in three families with isolated hypogonadotrophic hypogonadism.PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included.MEASUREMENTS DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene.RESULTS A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH‐R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH‐R gene.CONCLUSIONS This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH‐R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH‐R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect.
Absence of mutations in the growth hormone (GH)‐releasing hormone receptor gene in GH‐secreting pituitary adenomas
Authors: Salvatori Roberto , Thakker Rajesh V. , Lopes M. Beatriz , Fan Xiaoguang , Eswara Jairam R. , Ellison David , Lees Peter , Harding Brian , Yang Inmyung , Levine Michael A. 
Published: March 2003

GH‐releasing hormone (GHRH) is a potent stimulator of somatotroph cell proliferation and GH secretion. GHRH acts via binding to a G‐protein coupled receptor (GPCR) (GHRH‐R), that activates adenylyl cyclase (AC) and increases growth and function of somatotroph cells. Indeed, a subset (30–40%) of somatotrophic adenomas contain somatic mutations of the GNAS1 gene that encodes the alpha subunit of the G‐protein (Gsα) that stimulates AC. As activating mutations of other GPCRs cause development of endocrine tumours, we hypothesized that somatic activating mutations of the GHRH‐R might provide the molecular basis for somatotroph cell proliferation in a subset of human GH‐secreting pituitary adenomas.We analysed genomic DNA isolated from 26 somatotrophinomas, 17 of which lacked activating mutations in the GNAS1 gene. We individually amplified via polymerase chain reaction all 13 coding exons and the exon‐intron boundaries of the GHRH‐R gene. We used denaturing gradient gel electrophoresis to search for abnormalities in exons 1 through 11. Abnormally migrating bands were subjected to direct sequencing. Exons 12 and 13, encoding for the intracellular C‐terminal domain, were subjected to direct sequencing.Mutations were not detected in any of the tumours, but a rare polymorphism in codon 225 corresponding to the third transmembrane domain (V225I) was discovered.GHRH‐R mutations are absent or rare in somatotrophinomas, and other mechanisms must explain the somatotroph cell proliferation in the adenomas that lack activating mutations in the GNAS1 gene.
Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO‐QOL) after different treatments
Authors: Terwee C. B. , Dekker F. W. , Mourits M.P. , Gerding M. N. , Baldeschi L. , Kalmann R. , Prummel M. F. , Wiersinga W. M. 
Published: March 2003

The Graves' ophthalmopathy quality of life questionnaire (GO‐QOL) is the first instrument available to measure health‐related quality of life (HRQL) of patients with Graves' ophthalmopathy. The main objective of this study was to define a minimal clinically important difference (MCID) in score on the GO‐QOL that can be considered an important improvement in HRQL by examining changes in GO‐QOL scores in patients who subjectively report improvement from their treatment. A secondary objective was to test the longitudinal validity of the GO‐QOL, using prespecified hypotheses about expected treatment effects.A prospective cohort study.We included 164 patients who were scheduled for radiotherapy (23), orbital decompression (10 for sight loss, 38 for exophthalmos), eye muscle surgery (31), eyelid lengthening (43) or blepharoplasty (19).Patients completed the GO‐QOL and three general HRQL questionnaires, before and three or six months after treatment, depending on the performed procedure. Clinical characteristics were collected from the medical records. Mean changes in GO‐QOL scores and effect sizes were calculated after different treatments, and in subgroups of responders and nonresponders according to clinical characteristics and according to the patients themselves.A clinical response to treatment was associated with a change in GO‐QOL scores of approximately 10–20 points after major treatments (radiotherapy or decompression), and with a change of approximately 3–10 points after minor surgery (eye muscle surgery, eyelid lengthening, blepharoplasty). Changes in GO‐QOL scores of about 6–10 points were considered important improvements by the patients themselves. The direction and amount of change in GO‐QOL scores after different treatments were in accordance with our prespecified hypotheses about treatment effects. Effect sizes in the GO‐QOL subscales were generally higher than effect sizes of the general HRQL subscales, supporting the longitudinal validity of the GO‐QOL.As a general guideline, one could consider a mean change of at least 6 points on one or both subscales an important change in daily functioning for patients. For more invasive therapies, a change of at least 10 points is recommended as a minimal clinically important difference.
The islet amyloid polypeptide (amylin) gene S20G mutation in Chinese subjects: Evidence for associations with type 2 diabetes and cholesterol levels
Authors: Lee S. C. , Hashim Y. , Li J. K. Y. , Ko G. T. C. , Critchley J. A. J. H. , Cockram C. S. , Chan J. C. N. 
Published: March 2003

BACKGROUND and OBJECTIVES There has been evidence that the S20G mutation in the islet amyloid polypeptide (amylin) gene may be associated with type 2 diabetes. In the present study, we investigated the distribution of the mutation in Hong Kong Chinese, and examined whether there was evidence for associations between the mutation and type 2 diabetes and/or metabolic profiles.SUBJECTS and METHODS This study involved 227 early and 235 late‐onset (defined as onset age ≤ 40 and > 40 years, respectively) type 2 diabetic patients, as well as 126 nondiabetic subjects. The mutation was detected using a PCR‐RFLP method.RESULTS We identified six (2·6%) and one (0·4%) patients heterozygous for the mutation from the early and late‐onset groups, respectively (P = 0·05). None of the nondiabetic subjects had the mutation. Insulin deficiency and poor glycaemic control were not common findings amongst carriers of the mutation. In the early onset group, the patients with the mutation had lower plasma levels of total (4·3 ± 0·9 mmol/l vs. 5·3 ± 1·1 mmol/l, P = 0·02) and low density lipoprotein (LDL)‐cholesterol (2·3 ± 0·7 mmol/l vs. 3·2 ± 0·9 mmol/l, P = 0·01) than those without the mutation.CONCLUSIONS Our data suggest that the islet amyloid polypeptide gene mutation might be associated with early occurrence of type 2 diabetes and lower plasma levels of total and low density lipoprotein‐cholesterol in the Chinese population.
Increased insulin sensitivity in young, growth hormone deficient children
Authors: Husbands Sandra , Ong Ken K. L. , Gilbert Jan , Wass John A. H. , Dunger David B. 
Published: March 2003

OBJECTIVE Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children.DESIGN AND PATIENTS Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety‐one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GH ≥ 20 IU/l).MEASUREMENTS The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity.RESULTS GH deficient children were more insulin sensitive than GH sufficient children (P = 0·004) and had lower glucose nadirs post‐insulin (P = 0·005). Subgroup analysis revealed that these differences were greater in younger (< 12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P < 0·05) compared to nonprimed tests.CONCLUSIONS Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.
Detection of a recurring mutation in the human growth hormone‐releasing hormone receptor gene
Authors: Salvatori Roberto , Aguiar‐Oliveira Manuel H. , Monte Luciana V. B. , Hedges Lora , Santos Norma L. , Pereira Rossana M. C. , Phillips John A. 
Published: March 2003

Summaryobjective Mutations in the gene encoding for the GH‐releasing hormone receptor (GHRHR) have been recently described in patients with familial isolated GH deficiency (IGHD) type IB. To date, all reported mutations have been found in kindreds sharing common ancestors. The only exception is a T to A transversion which causes a substitution of histidine for leucine in codon 144 (L144H) and creates a DraIII restriction site. This mutation was described in two families with different ethnic background residing in two different continents (Europe and North America).design We searched for GHRHR mutations in a new family with IGHD from a third continent (South America) and found the affected individuals to be homozygous for the same L144H change. We performed linkage analysis with intra‐ and para‐genic polymorphisms to determine if the three families carrying the L144H allele are related.results Linkage analysis studies demonstrated that one of the three families does not share the same para‐ and intragenic GHRHR polymorphisms with the other two.conclusions The L144H mutation has arisen at least twice and should be considered for initial genetic analysis in patients with familial IGHD in whom the a GHRHR mutation is suspected.