bluuebunny/crossref_metadata_2025_split huggingface dataset:
The improvement of insulin resistance in patients with adrenal incidentaloma by surgical resection
Authors: Midorikawa Sanae , Sanada Hironobu , Hashimoto Shigeatsu , Suzuki Takayuki , Watanabe Tsuyoshi 
Published: March 2003

OBJECTIVE Several recent studies have indicated that patients with adrenal incidentaloma often have disturbed glucose tolerance or/and hypertension. It is unclear whether these metabolic conditions could be caused by adrenal incidentaloma. We investigated the prevalence of disturbed glucose tolerance, hypertension and insulin resistance in the patients with non‐functioning adrenal incidentaloma and evaluated the changes of the parameters such as glucose tolerance, blood pressure and insulin sensitivity after adrenalectomy.PATIENTS AND METHODS Among 15 patients with incidentally discovered adrenal tumours in our department from 1996 to 1999, 4 patients were diagnosed as having pre‐clinical Cushing's syndrome and the other 11 as having non‐functioning tumours based on detailed endocrinological examinations including dexamethasone suppression testing. Four tumours with pre‐clinical Cushing's syndrome and 8 tumours out of 11 patients with non‐functioning tumours were diagnosed histopathologically as adrenocortical adenomas and the other 3 as of non‐adrenal origin including a myelolipoma, an adrenal vascular cyst and an endothelioma. The prevalence of disturbed glucose tolerance was determined with an oral glucose tolerance test, and insulin sensitivity was evaluated by the method of steady state of plasma glucose (SSPG).RESULTS All 12 patients with adrenocortical adenoma exhibited insulin resistance based on the SSPG (6·9–13·2 mmol/l). Before surgical removal of the tumours, the SSPG titre was relatively higher in the patients with pre‐clinical Cushing's syndrome than in those with non‐functioning with adrenocortical adenoma (mean value 11·65 vs. 8·99 mmol/l), whereas 2 of the 3 patients with non‐adrenocortical tumours did not have insulin resistance. Among the 12 patients with adrenocortical adenoma, 7 (58%) and 9 (75%) patients exhibited hypertension and disturbed glucose tolerance, respectively. After removal of the tumours, SSPG of the patients with adrenocortical adenoma, but not that of the other 3 patients with non‐cortical tumours, was significantly decreased compared to pre‐adrenalectomy values. There are no significant differences in the changes of SSPG titres between in pre‐clinical Cushing's syndrome and in non‐functioning adrenocortical adenoma. Systolic blood pressure, but not diastolic blood pressure, was also significantly decreased in the patients with adrenocortical adenoma.CONCLUSION High prevalences of disturbed glucose tolerance, insulin resistance and hypertension were found among the patients with non‐functioning adrenocortical tumours. Adrenocortical adenoma may be one of the risk factors for insulin resistance that is believed to induce disturbed glucose tolerance and/or hypertension. Therefore, it is useful to evaluate insulin resistance for the patients with adrenal incidentalomas since results are likely to be helpful in deciding whether to remove the tumour by surgery.
Ras mutations are rare in solitary cold and toxic thyroid nodules
Authors: Krohn Knut , Reske Alexander , Ackermann Frank , Müller Anke , Paschke Ralf 
Published: March 2003

OBJECTIVE Activation of ras proto‐oncogenes as a result of point mutations is detectable in a significant percentage of most types of tumour. Similar to neoplasms of other organs, mutations of all three ras genes can be found in thyroid tumours. H‐, K‐ and N‐ras mutations have been detected in up to 20% of follicular adenomas and adenomatous nodules which were not functionally characterized. This raises the question as to whether ras mutations are specific for hypofunctional nodules and TSH receptor mutations for hyperfunctioning nodules.DESIGN To investigate ras and TSH receptor mutations with respect to functional differentiation we studied 41 scintigraphically cold nodules and 47 toxic thyroid nodules. To address the likelihood of a somatic mutation we also studied the clonal origin of these tumours.MEASUREMENTS Genomic DNA was extracted from nodular and surrounding tissue. Mutational hot spots in exons 1 and 2 of the H‐ and K‐ras gene were PCR amplified and sequenced using big dye terminator chemistry. Denaturing gradient gel electrophoresis (DGGE) was used to verify sequencing results for the H‐ras gene and to analyse the N‐ras gene because its greater sensitivity in detecting somatic mutations. Clonality of nodular thyroid tissue was evaluated using X‐Chromosome inactivation based on PCR amplification of the human androgen receptor locus.RESULTS Monoclonal origin was detectable in 14 of 23 informative samples from cold thyroid nodules. In toxic thyroid nodules the frequency of clonal tissue was 20 in 30 informative cases. Only one point mutation could be found in the N‐ras gene codon 61 (Gly to Arg) in a cold adenomatous nodule which was monoclonal. In toxic thyroid nodules no ras mutation was detectable.CONCLUSION Our study suggests that ras mutations are rare in solitary cold and toxic thyroid nodules and that the frequent monoclonal origin of these tumours implies somatic mutations in genes other than H‐, K‐ and N‐ras.
Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas
Authors: Kim Kyongsong , Arai Keiko , Sanno Naoko , Osamura R. Yoshiyuki , Teramoto Akira , Shibasaki Tamotsu 
Published: March 2003

OBJECTIVE The level of growth hormone (GH), growth hormone secretogogue (GHS) and GHS receptor (GHSR) messenger ribonucleic acid (mRNA) expression has been reported as being higher in GH‐producing pituitary adenomas than in other types of pituitary adenomas. Recently, ghrelin, an endogenous ligand specific for GHSR, was isolated. Therefore, we attempted to clarify whether ghrelin mRNA is expressed in various types of human pituitary adenoma by competitive reverse transcription‐polymerase chain reaction (RT‐PCR). We also examined the relationship between the levels of ghrelin or GHSR mRNA and hormonal and tumour characteristics in patients with pituitary adenomas.PATIENTS Pituitary adenoma tissue was obtained at surgery from 13 patients with acromegaly, 4 with prolactinomas, 5 with gonadotrophin (Gn)‐producing adenomas, 4 with non‐functioning adenomas, 2 with ACTH‐producing adenomas and 2 with TSH‐producing adenomas.METHODS The expression levels of human ghrelin mRNA and GHSR mRNA were quantified using a competitive RT‐PCR method.RESULTS Ghrelin mRNA was detected in all pituitary adenoma tissues examined, with the highest mean level detected in non‐functioning adenomas, a moderate level in GH‐producing adenomas and Gn‐producing adenomas, and the lowest level in prolactinomas. The level of ghrelin mRNA expression in GH‐producing adenomas correlated negatively with the size of the adenoma (n = 13) (r = − 0·756, P = 0·0028). Furthermore, the mean level of ghrelin mRNA expression in high‐grade (III and IV of Hardy classification) GH‐producing adenomas was significantly lower than that in low‐grade (I and II) GH‐producing adenomas (P = 0·0016). GHSR mRNA was also detected in all pituitary adenomas with the highest mean level in GH‐producing adenomas, a moderate level in nonfunctioning adenoma, and the lowest level in prolactinoma and Gn‐producing adenomas.CONCLUSIONS Ghrelin mRNA, in addition to GHSR mRNA, is expressed in various types of pituitary adenoma with different levels of expression in each type. Our findings suggest that ghrelin produced in pituitary adenoma may play some role in the mechanism underlying the development of adenoma cells through autocrine and/or paracrine pathways.
A novel mutation (N233K) in the transactivating domain and the N756S mutation in the ligand binding domain of the androgen receptor gene are associated with male infertility*
Authors: Giwercman Yvonne Lundberg , Nikoshkov Andrej , Byström Birgitta , Pousette Åke , Arver Stefan , Wedell Anna 
Published: March 2003

OBJECTIVE Resistance to androgens has been suggested as a possible cause of male infertility. This hypothesis is based mainly on binding studies in genital skin fibroblasts but the molecular evidence is sparse.DESIGN Molecular studies of the androgen receptor gene were performed in 10 azoo‐ or oligozoospermic men, presenting with clinical signs of low androgen activity—poor virilization and high serum LH despite elevated testosterone levels, but without genital malformations.PATIENTS Ten men with serum LH >10 IU/l and testosterone >30 nmol/l as well as a low sperm concentration < 20 × 106/ml.MEASUREMENTS Genomic DNA was prepared from peripheral leucocytes and PCR‐amplification of the coding region of androgen receptor was performed, followed by direct sequencing. Identified mutations were reconstructed by site‐directed mutagenesis and the functional properties of the mutants were analysed, using transient expression in COS‐1 cells and subsequent transactivation assays. Hormone binding assays were performed in genital skin fibroblasts from the patients.RESULTS Two of the 10 men were shown to have a mutation in the androgen receptor gene. Subject 1, who presented with azoospermia, serum testosterone (T) 50 nmol/l and LH 20 IU/l, had a mutation in exon 1, changing amino acid asparagine 233 to lysine (N233K). In fibroblasts cultured from genital skin, the receptor affinity for 5α‐dihydrotestosterone (DHT) was normal as compared to healthy controls, but the receptor–hormone complex was thermolabile at 42°C. Subject 2 exhibited severe oligozoospermia and a similar endocrine pattern (T = 50 nmol/l and LH = 25 IU/l). He had a mutation in exon 5 changing asparagine 756 to serine (N756S). The affinity for DHT in cultured genital fibroblasts from this patient was reduced. Transactivation was abnormal for both mutants, N233K reaching 46% and N756S 38% of wild type activity when stimulated with 10 nmol/l DHT.CONCLUSIONS Androgen receptor mutations may affect sperm production without resulting in genital malformations. Thus, in infertile men with a clinical presentation of poor androgen activity and an endocrine profile compatible with androgen resistance, mutations in the androgen receptor should be taken into consideration.
Possible association but no linkage of the HSD11B2 gene encoding the kidney isozyme of 11β‐hydroxysteroid dehydrogenase to hypertension in Black people
Authors: White Perrin C. , Agarwal Anil K. , Li Airong , Nikkila Heli , Pratt J. Howard , Caulfield Mark , Clark Adrian , McTernan Claire , Stewart Paul M. 
Published: March 2003

OBJECTIVE The HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11β‐hydroxysteroid dehydrogenase is mutated in the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of salt‐sensitive hypertension. This gene is thus a logical candidate locus for risk of essential hypertension.DESIGN AND METHODS Because hypertension in Black people tends to be of the low‐renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro‐American (59 kindreds) and Afro‐Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0·84) CA repeat polymorphism in the first intron of HSD11B2. Linkage was assessed by the affected pedigree member method.RESULTS No linkage of hypertension to this locus could be demonstrated, but statistically significant allelic associations were noted.CONCLUSIONS HSD11B2 does not have a strong influence on the development of essential hypertension in Black people, but weaker effects on blood pressure cannot be ruled out.
Germline sequence variant S836S in the RET proto‐oncogene is associated with low level predisposition to sporadic medullary thyroid carcinoma in the Spanish population
Authors: Ruiz Agustín , Antiñolo Guillermo , Fernández Raquel M. , Eng Charis , Marcos Irene , Borrego Salud 
Published: March 2003

OBJECTIVE The molecular basis of sporadic medullary thyroid carcinoma (MTC) remains elusive. While germline gain‐of‐function mutations in the RET proto‐oncogene cause hereditary MTC, somatic activating RET mutations and loss of heterozygosity of markers in various chromosomal regions representing deletions of tumour suppressor genes, have been described in a variable number of sporadic MTC. A previous report suggested that the presence of a germline variant at RET codon 836 (S836S) was associated with the development of sporadic MTC and, furthermore, that the presence of S836S was highly correlated with somatic RET M918T mutation in the MTC. Thus, we sought to determine if the S836S variant would be associated with sporadic MTC from a completely different population base, that of Andalucia.DESIGN This is a case–control study to determine whether the presence of RET germline S836S is correlated with sporadic MTC in Andalucia.PATIENTS Thirty‐two patients with sporadic MTC from the Andalucia region of Spain, serviced by our University Hospital, were ascertained throughout the period 1995–99. Sporadic MTC was defined as a lack of personal or family history suggestive of multiple endocrine neoplasia type 2 (MEN 2) and lack of germline RET mutations which define any MEN 2 subtype. A region and race matched cohort of 250 controls was also obtained.MEASUREMENTS The frequency of the S836S allele was determined in cases and controls and compared using the standard chi‐squared statistic and Fisher's exact test.RESULTS The polymorphic allele frequency at codon 836 in the control population (18/500 chromosomes, 3·6%) differed significantly from the MTC case cohort, 9·3% of case chromosomes (six of 64 alleles, Fisher's exact test, two‐tailed, P = 0·043).CONCLUSIONS Germline RET S836S variant is associated with a two‐ to three‐fold risk of sporadic MTC in the Spanish population, in accordance with a previous study based on German cases. Our observations suggest that this phenomenon might be universal and not limited to Germany.
Weight gain following treatment of hyperthyroidism
Authors: Dale J. , Daykin J. , Holder R. , Sheppard M. C. , Franklyn J. A. 
Published: March 2003

OBJECTIVE Patients frequently express concern that treating hyperthyroidism will lead to excessive weight gain. This study aimed to determine the extent of, and risk factors for, weight gain in an unselected group of hyperthyroid patients.DESIGN and SUBJECTS We investigated 162 consecutive hyperthyroid patients followed for at least 6 months. Height, weight, clinical features, biochemistry and management were recorded at each clinic visit.RESULTS Documented weight gain was 5·42 ± 0·46 kg (mean ± SE) and increase in BMI was 8·49 ± 0·71%, over a mean 24·2 ± 1·6 months. Pre‐existing obesity, Graves' disease causing hyperthyroidism, weight loss before presentation and length of follow‐up each independently predicted weight gain. Patients treated with thionamides or radioiodine gained a similar amount of weight (thionamides, n = 87, 5·16 ± 0·63 kg vs. radioiodine, n = 62, 4·75 ± 0·57 kg, P = 0·645), but patients who underwent thyroidectomy (n = 13) gained more weight (10·27 ± 2·56 kg vs. others, P = 0·007). Development of hypothyroidism (even transiently) was associated with weight gain (never hypothyroid, n = 102, 4·57 ± 0·52 kg, transiently hypothyroid, n = 29, 5·37 ± 0·85 kg, on T4, n = 31, 8·06 ± 1·42 kg, P = 0·014). This difference remained after correcting for length of follow‐up. In the whole cohort, weight increased by 3·95 ± 0·40 kg at 1 year (n = 144) to 9·91 ± 1·62 kg after 4 years (n = 27) (P = 0·008), representing a mean weight gain of 3·66 ± 0·44 kg/year.CONCLUSION We have demonstrated marked weight gain after treatment of hyperthyroidism. Pre‐existing obesity, a diagnosis of Graves' disease and prior weight loss independently predicted weight gain and weight continued to rise with time. Patients who became hypothyroid, despite T4 replacement, gained most weight.
GH administration and discontinuation in healthy elderly men: effects on body composition, GH‐related serum markers, resting heart rate and resting oxygen uptake
Authors: Lange Kai Henrik Wiborg , Isaksson Fredrik , Rasmussen Michael Højby , Juul Anders , Bülow Jens , Kjær Michael 
Published: March 2003

BACKGROUND AND OBJECTIVES GH administration results in increased lean body mass (LBM), decreased fat mass (FM) and increased energy expenditure (EE). GH therapy may therefore have potential benefits, especially in the elderly, who are known to have decreased function of the GH/IGF‐I axis. Several studies have focused on effects of GH administration in the elderly in the last decade. However, very limited information is available regarding changes in body composition and EE upon GH discontinuation in the elderly. The present study therefore investigated the effects of 12 weeks of GH administration and subsequent discontinuation on body composition, resting oxygen uptake (VO2), resting heart rate (HR) and GH related serum markers in healthy elderly men.SUBJECTS AND METHODS Sixteen healthy men [age 74 ± 1 years (mean ± SEM), height 174·2 ± 1·6 cm, body weight 80·7 ± 2·6 kg, body fat 27·5 ± 1·1%] completed the study protocol. Recombinant human GH (1·80 ± 0·24 IU/day) was administered for 12 weeks in a single‐blinded, placebo‐controlled design. Body composition (dual energy X‐ray absorptiometry), resting VO2 (indirect calorimetry), resting HR (telemetry) and serum IGF‐I, IGF‐II, IGFBP‐3 and acid labile subunit (ALS) were measured at baseline, after 12 weeks of GH administration and, additionally in the GH group, 1, 2, 3, 4, 5 and 9 days after GH discontinuation.RESULTS Body weight was unchanged from baseline to 12 weeks in both groups. However, GH administration caused a decrease in FM (3·4 ± 1·0 kg, P < 0·012), paralleled by a similar increase in LBM (3·2 ± 0·4 kg, P < 0·0002). Resting VO2 and resting HR increased by 31 ± 3·6% and 7·3 ± 1·9 per minute, respectively, in the GH‐group, where significant increases in serum IGF‐I, IGFBP‐3 and ALS also were noted. None of the above parameters changed in the placebo group. Within 2–3 days after GH discontinuation, the GH related serum markers and resting HR returned to baseline levels, whereas resting VO2 remained elevated even 9 days after GH discontinuation. In addition, GH discontinuation caused a significant decrease in body weight (1·86 ± 0·35 kg), derived exclusively from a decrease in LBM (1·63 ± 0·43 kg), while the decreased FM was maintained (12 weeks: 17·93 ± 1·65 kg, +9 days: 17·74 ± 1·62 kg).CONCLUSIONS The increases in serum IGF‐I, IGFBP‐3, ALS and resting heart rate induced by 12 weeks of GH administration in elderly men returned to baseline levels within 2–3 days after GH discontinuation. However, resting VO2 remained elevated for a longer period. GH administration reduced fat mass but maintained body weight by increasing lean body mass. In contrast, 9 days of GH discontinuation reduced body weight exclusively by reducing lean body mass.
Cytotoxic T lymphocyte antigen 4 gene polymorphism confers susceptibility to Type 1 diabetes in Japanese children: analysis of association with HLA genotypes and autoantibodies
Authors: Kikuoka Noriko , Sugihara Shigetaka , Yanagawa Tatsuo , Ikezaki Ayako , Kim Hye Sook , Matsuoka Hisafumi , Kobayashi Yasuyuki , Wataki Kunio , Konda Susumu , Sato Hirokazu , Miyamoto Shigeki , Sasaki Nozomu , Sakamaki Tateo , Niimi Hiroo , Murata Mitsunori 
Published: March 2003

OBJECTIVE Although the polymorphisms of the cytotoxic T lymphocyte antigen 4 (CTLA4) gene have been shown to be associated with Type 1 diabetes in Caucasians, some conflicting results have been reported among subjects of different ethnic backgrounds. We examined a CTLA4 polymorphism and its relationship to human leucocyte antigen (HLA) genotypes and autoantibodies for glutamic acid decarboxylase 65 (GAD65) and IA‐2 in Japanese children with Type 1 diabetes.SUBJECTS AND MEASUREMENTS The study group consisted of 125 childhood‐onset Japanese subjects (50 males, 75 females) with Type 1 diabetes. The CTLA4 A/G polymorphism at position 49 was analysed using a PCR‐restriction fragment length polymorphism (PCR‐RFLP) method. The HLA‐DRB1 and DQB1 genotypes were defined by DNA analysis using PCR‐sequence‐specific oligonucleotide (PCR‐SSO) probes. The GAD65 autoantibody (GAD65Ab) and IA‐2 autoantibody (IA‐2Ab) titres were measured using radioimmunoassay.RESULTS The distribution of genotype frequencies differs between subjects with Type 1 diabetes (GG: 46%, AG: 50%, AA: 5%) and controls (GG: 39%, AG: 44%, AA: 17%) (P < 0·01). The frequency of the G allele is higher in the diabetes group than in the controls (P < 0·05). When the subjects were subdivided according to HLA genotype, the two major HLA high‐risk groups, with DR9‐DQ9 and DR4‐DQ4, that are unique to Japanese populations showed no difference in their CTLA4 polymorphism frequencies. Although no association between the CTLA4 polymorphism and the prevalence of GAD65Ab was found, CTLA4 GG subjects that had been newly diagnosed (< 9 months) had significantly higher levels of autoantibodies than AG subjects (P < 0·01). The prevalence and titres of IA‐2Ab were not associated with the CTLA4 polymorphism.CONCLUSIONS The CTLA4 gene might confer a susceptibility to childhood‐onset Type 1 diabetes in the Japanese population. The association between this CTLA4 polymorphism and the HLA genotype was similar for both major groups with HLA high‐risk alleles. CTLA4 might contribute to the humoral immune response to GAD in newly diagnosed subjects.
Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain
Authors: Regal Milagros , Páramo Concepción , Sierra José M. , García‐Mayor Ricardo V. 
Published: March 2003

OBJECTIVE To determine the prevalence and incidence of hypopituitarism in the general population.POPULATION The study population comprised an average population sample of 146 000 adult inhabitants in South Galicia (northwestern Spain). The Medical Register of the General Hospital of Vigo ensured virtually complete case ascertainment for diagnosed hypopituitarism in this sample population. Only patients residing in the study area were included. The diagnosis of hypopituitarism was based on baseline and hormonal dynamic tests.DESIGN The study comprised two cross‐sectional surveys, the first from January to December 1992 and the second from January to December 1999, together with a longitudinal survey performed between January 1993 and December 1999.MAIN RESULTS In the first survey the prevalence of hypopituitarism was 29/100 000 (CI, 19·88–37·72), without sex differences. In the second survey, the prevalence observed was higher than in the first, 45·5/100 000 (CI, 34·92–56·08). In the second survey, which included almost all cases registered in the first study, the cause of hypopituitarism was a pituitary tumour in 61%, a non‐pituitary tumour in 9% and a non‐tumour cause in 30%. Around 50% of patients had 3–5 pituitary hormonal deficiencies, with LH/FSH being the most prevalent. Patients with tumour‐induced hypopituitarism showed a tendency to suffer GH deficiency more frequently than those due to non‐tumour causes. In the longitudinal study with a population of 1020 764 people‐years of observation, the average annual incidence rate of hypopituitarism was 4·21 cases/100 000 (CI, 2·95–5·47), with this incidence being similar for both sexes. The annual incidence of hypopituitarism remained stable during the study period.CONCLUSION We present for the first time data on the prevalence and incidence of hypopituitarism in the general adult population. These patients showed a tendency to suffer LH/FSH deficiency as the most prevalent hormone deficit. Furthermore, patients with hypopituitarism due to a tumour or its treatment showed a greater tendency to suffer GH deficiency than those with a non‐tumour cause. These data may be useful for producing a rational programme for patients suffering from this condition and also for comparison with future data in our country and elsewhere in the world.