bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic analysis of the MEN1 gene and HPRT2 locus in two Italian kindreds with familial isolated hyperparathyroidism
Authors: Cetani Filomena , Pardi Elena , Giovannetti Anna , Vignali Edda , Borsari Simona , Golia Franco , Cianferotti Luisella , Viacava Paolo , Miccoli Paolo , Gasperi Maurizio , Pinchera Aldo , Marcocci Claudio 
Published: March 2003

SummaryOBJECTIVES Familial hyperparathyroidism may occur as part of hereditary syndromes, including multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2A), hyperparathyroidism‐jaw tumour (HPT‐JT) syndrome and familial isolated hyperparathyroidism (FIHP). It is unclear whether the latter is a distinct genetic entity or a variant of MEN1 or HPT‐JT, where, because of reduced penetrance, only primary hyperparathyroidism (PHPT) is present. In the present study, we describe two unrelated Italian kindreds with FIHP, in which the clinical, histopathological and genetic analyses of the MEN1 gene and HPRT2 locus at 1q21‐32 suggest that both might be a variant of MEN1 and HPT‐JT syndromes.PATIENTS AND DESIGN We studied 16 members, aged 14–50 years, of two unrelated kindreds with FIHP. Genomic DNA was isolated from peripheral blood leucocytes in all family members, and from parathyroid tissue in those who underwent parathyroidectomy.MEASUREMENTS Ionized calcium and PTH were measured in all family members. The nine coding exons and 16 splice junctions of the MEN1 gene from constitutional DNA were amplified by the polymerase chain reaction (PCR) and sequenced. Parathyroid glands were obtained from five subjects. Allelic deletions (loss of heterozygosity, LOH) of chromosomes 11q13 and 1q21‐q32 were assessed using PYGM and D11S449, and D1S215, D1S222, D1S428, D1S412, D1S413 and D1S477, respectively. Forward primers were conjugated with 5′ fluorescent dye. PCR products were analysed using an ABI PRISM 310 sequencer.RESULTS Five members of family 1 and three of family 2 had PHPT. A heterozygous deletion of 1 bp of the MEN1 gene in exon 10 (1785delA) was found in affected members of family 1. No MEN1 gene mutation was found in any member of family 2. LOH at 11q13 was observed in family 1 tumours, but not in those from family 2. Studies at 1q21‐32 showed LOH in two family 2 tumours, whereas a retained heterozygosity was found in the remaining member. No LOH at 1q21‐32 was found in family 1 tumours. The pathology of family 1 showed chief cell hyperplasia with a diffuse‐nodular pattern of growth. Cut surface showed no cystic structures. Typical parathyroid adenoma was diagnosed in one member of family 2 and atypical adenoma in the remaining two. These tumours showed cystic structures.CONCLUSIONS In conclusion, we describe two unrelated kindreds with FIHP which, on the basis of histopathological and genetic studies, could be labelled as variants of the MEN1 and HPT‐JT syndromes, respectively. Therefore, an extensive analysis of the genes involved in these diseases should be performed in families with familial isolated hyperparathyroidism to identify the subset linked to the MEN1 gene or to the HPRT2 locus.
Radio‐frequency ablation for symptom control in a patient with metastatic pancreatic insulinoma
Authors: Scott Adrian , Hinwood David , Donnelly Richard 
Published: March 2003

SummaryMalignant insulinomas are very rare endocrine tumours with a variable clinical course. We describe a 51‐year‐old man who had two large insulinomas resected from the body of the pancreas and 19 years later, having again become symptomatic, was found to have hepatic metastases. Medical treatment with diazoxide and octreotide failed to control his symptoms, but repeated hepatic embolization effected both symptomatic and biochemical improvements for a further 5 years. When symptoms recurred but further embolization failed to control his symptoms the hepatic metastases were treated by outpatient percutaneous radio‐frequency ablation. He remains symptom‐free 18 months later and levels of insulin and pro‐insulin have nearly normalized. The survival, with liver metastases, for 27 years in a man with a malignant insulinoma has not been described previously. Malignant insulinoma may follow a rather indolent course and symptoms respond well to locally destructive therapies. Hepatic embolization is less traumatic than hepatic lobe resection and radio‐frequency ablation offers an alternative if vascular access to the tumour is no longer possible.
Effects of GH replacement on endothelial function and large‐artery stiffness in GH‐deficient adults: a randomized, double‐blind, placebo‐controlled study
Authors: Smith J. C. , Evans L. M. , Wilkinson I. , Goodfellow J. , Cockcroft J. R. , Scanlon M. F. , Davies J. S. 
Published: March 2003

Summaryobjectives Hypopituitary adults with growth hormone deficiency (GHD) have an increased cardiovascular mortality, although the mechanisms remain unclear. Endothelial dysfunction, characterized by reduced nitric oxide (NO) bioavailability, is a key early event in atherogenesis and is associated with increased vascular smooth muscle tone and arterial stiffening.design and patients In a randomized, double‐blind, placebo‐controlled study, we investigated the effects of GH replacement on endothelial function and large‐artery stiffness in 32 GHD adults (19 males, 13 females) (age range 19–64 years) over a 6‐month period. Thirty‐two age‐ and sex‐matched healthy controls were also studied.measurements Endothelial function was assessed using ultrasonic wall tracking to measure flow‐mediated dilatation (FMD) of the brachial artery. Large artery stiffness was assessed by pulse wave analysis of the radial artery pressure waveform, allowing determination of the corresponding central arterial pressure waveform and derivation of the augmentation index. Fasting lipid profiles, glucose and insulin were also measured.results At baseline, FMD (mean ± SD) was impaired in GH‐deficient subjects vs. controls (3·4 ± 2·3 vs. 5·7 ± 2·0%, P < 0·0001), although endothelium‐independent dilatation was similar. The augmentation index was higher in GH‐deficient subjects vs. controls (23 ± 12 vs. 14 ± 14%, P < 0·01). GH‐deficient subjects had higher LDL cholesterol (4·1 ± 0·8 vs. 3·5 ± 0·8 mmol/l, P < 0·01) and lower HDL cholesterol (1·1 ± 0·3 vs. 1·4 ± 0·4 mmol/l, P < 0·01). In GH‐deficient subjects, there were inverse correlations between LDL cholesterol and FMD (r = –0·40, P < 0·05) and between FMD and the augmentation index (r = – 0·58, P < 0·01). Regression analysis identified FMD as an independent predictor of the augmentation index (P < 0·0001). In comparison with baseline, GH replacement resulted in an increase in FMD (5·0 ± 2·6 vs. 2·8 ± 1·9%, P < 0·01). There were decreases in central aortic systolic pressure (117 ± 15 vs. 123 ± 17 mmHg, P < 0·01), diastolic pressure (82 ± 10 vs. 86 ± 8 mmHg, P < 0·01) and the augmentation index (22 ± 8%vs. 26 ± 10%, P < 0·05) despite unchanged brachial pressure indices. LDL cholesterol also decreased (3·5 ± 0·8 vs. 4·2 ± 0·8 mmol/l, P < 0·01). There were no significant changes in the placebo group.conclusions Adult GHD is associated with endothelial dysfunction and increased large‐artery stiffness. An improvement in endothelial function and a reduction in arterial stiffness following GH replacement suggests an important therapeutic role for GH in reducing cardiovascular risk associated with adult GHD.
Increased menin expression in sporadic pituitary adenomas
Authors: Wrocklage Christian , Gold Heidrun , Hackl Wolfgang , Buchfelder Michael , Fahlbusch Rudolf , Paulus Werner 
Published: March 2003

Summarybackground Germline mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour‐suppressor gene are responsible for multiple endocrine neoplasia type 1, and menin, the MEN1 gene product, is usually downregulated or truncated in MEN1‐associated adenomas. In contrast, exonic MEN1 mutations seem to be very rare in sporadic (MEN1‐unrelated) pituitary adenomas, and it has been suggested that menin does not play a major role in these tumours. However, menin might be involved in sporadic adenoma tumorigenesis by downregulation through intronic mutations, epigenetic, posttranscriptional or posttranslational mechanisms.patients and measurements We screened MEN1 coding regions and flanking intronic sequences of 136 sporadic pituitary adenomas by temporal temperature gradient gel electrophoresis (TTGE) and studied menin expression by immunoblotting in 11 of these tumours.results Sequencing of DNAs showing aberrant migration on TTGE revealed five somatic MEN1 mutations, including two missense mutations (F134L, E530K), a 2‐bp deletion in exon 10 (c.1567–1568del) leading to a premature stop codon, and two 3‐bp deletions in intron 5 (g.5236–5238del, g.5237–5239del). These mutations have not been reported previously in studies analysing the MEN1 gene. Immunoblotting showed menin upregulation in all adenomas examined (including one case with a missense mutation) from 1·7‐fold to 10·4‐fold (mean, 4·2‐fold) compared to non‐neoplastic adenohypophysis.conclusions Our data suggest that neither MEN1 mutations nor menin downregulation play a significant role in the development of sporadic pituitary adenomas.
Pituitary tumours are multiclonal from the outset: evidence from a case with dural metastases
Authors: Buch H. , El‐Hadd T. , Bicknell J. , Simpson D. J. , Farrell W. E. , Clayton R. N. 
Published: March 2003

SummaryIn 1992 a 54‐year‐old man underwent transsphenoidal adenomectomy to remove a clinically nonfunctioning pituitary adenoma during which there was a transient cerebrospinal fluid (CSF) leak. He received radiotherapy to a small residual remnant. Follow‐up magnetic resonance imaging (MRI) scan in 1997 showed an increase in the tumour in the pituitary stalk region and an additional intradural lesion at C1 level. In the absence of neurological symptoms and signs, an observational policy was followed. By 1999 the cervical dural lesion had enlarged and laminectomy was performed, during which three intradural lesions were removed. Histology and immunohistochemistry of the metastases were identical to those of the initial pituitary adenoma. Follow‐up MRI scan showed extension of the pituitary remnant above the chiasma, requiring transfrontal surgery. Operation was complicated by secondary brain haemorrhage from which the patient died. Autopsy revealed a small amount of residual tumour at the top of the stalk and several small intradural tumour nodules at the level of the foramen magnum. Genetic analysis of the initial pituitary tumour identified significant allelic losses in keeping with its invasive nature, while that of the metastases indicated a separate clone as shown by retention of alleles lost in the primary tumour. The regrown pituitary tumour also appeared to be of a different clone to the initial tumour and the same as two of three of the first metastases (C1 level). The foramen magnum metastasis showed the same loss of heterozygosity (LOH) pattern as one of the original C1 metastases and the pituitary tumour tissue obtained at autopsy. We speculate that at the initial pituitary surgery, cells seeded into the CSF and grew in the dura. These cells were from a different clone, implying that the original pituitary tumour contained at least two clones, possibly three, providing evidence for the contemporaneous oligoclonality of the original pituitary tumour.
Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance
Authors: Mauvais‐Jarvis Franck , Kulkarni Rohit N. , Kahn C. Ronald 
Published: March 2003

Summaryobjective The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic β‐cells to compensate by adequate insulin secretion.design Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance.results Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue‐specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue‐specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin‐responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic β‐cells and brain in the development of insulin deficiency and obesity.
Low goitre prevalence among users of oral contraceptives in a population sample of 3712 women
Authors: Knudsen Nils , Bülow Inge , Laurberg Peter , Perrild Hans , Ovesen Lars , Jørgensen Torben 
Published: March 2003

Summaryobjective Goitre occurs primarily in women. As oestrogens may be an aetiologic factor, the use of oral contraceptives (OC) could be associated with an increased risk of goitre. This is supported by experimental data, but a recent population study suggested decreased thyroid volumes among users of OC.design Cross‐sectional, observational study.participants A random population sample of 3712 women from two Danish cities.measurements Ultrasound and clinical examination of the thyroid, measurement of serum TSH, T3, T4 and thyroglobulin, and personal interviews with registration of use of OC or post‐menopausal oestrogen therapy. Data were analysed in linear models and logistic regression adjusting for age and iodine status.results Thyroid volume was lower among users than non‐users of OC, 11·1 ml vs. 12·1 ml (P < 0·001). Use of OC was correspondingly associated with a reduced prevalence of thyroid enlargement on ultrasound (odds ratio 0·53, 95% confidence interval 0·37–0·74) and of palpable and visible goitre (OR 0·24, 95% CI 0·07–0·81). Serum TSH was 1·24 mU/l in non‐users of OC and 1·35 mU/l in users (P = 0·002). The percentage of goitre cases prevented by OC compared to a hypothetical population without use of OC was 29%. Post‐menopausal oestrogen therapy showed similar, but statistically non‐significant, associations.conclusion Use of oral contraceptives was associated with a lower thyroid volume and reduced risk of goitre, and clinically evident goitre was four times more frequent among non‐users than among users of oral contraceptives.
Pitfalls in pituitary diagnosis: peculiarities of three cases
Authors: Glezer A. , D’Alva C. B. , Salgado L. R. , Musolino N. R. , Serafini P. , Vieira J. G. , Bronstein M. D. 
Published: March 2003

SummaryDue to the increasing availability and sensitivity of diagnostic methods, biochemical and imaging abnormalities of pituitary function and anatomy are becoming more frequent. Hyperprolactinaemia was found in three women without any prolactin (PRL) related clinical features. All three patients had normal libido, regular menses with evidence of ovulation, no galactorrhoea, and normal FSH, LH, TSH and free T4 serum levels. Magnetic resonance imaging (MRI) of the sellar region showed images that were compatible with pituitary microadenomas in all three cases. Due to the discordance between laboratory and clinical features, we searched for the presence of PRL aggregates with high molecular weight and low biological activity (macroprolactinaemia). Initially, we screened with a polyethylene glycol precipitation method, and then confirmed the presence of macroprolactinaemia by chromatography. All three cases screened positive for the presence of macroprolactinaemia. MRI alterations, compatible with pituitary microadenomas, may be due to true microincidentalomas, normal anatomical variations or imaging artefacts. In conclusion, we have described the presence of double diagnostic pitfalls that might lead to unnecessary medical or surgical intervention.
Biochemical markers of growth hormone (GH) sensitivity in children with idiopathic short stature: individual capacity of IGF‐I generation after high‐dose GH treatment determines the growth response to GH
Authors: Kamp G. A. , Zwinderman A. H. , Van Doorn J. , Hackeng W. , Frölich M. , Schönau E. , Wit J. M. 
Published: March 2003

Summaryobjective and patients  To assess multiple dose–response relationships between three GH doses (1·5, 3·0 and 6·0 IU/m2) and nine different biochemical markers of GH sensitivity in a well‐defined group of 17 children with idiopathic short stature (ISS).design and measurements  Serum levels of IGF‐I, IGF‐II and IGFBP‐3, and peripheral markers leptin, C‐terminal propeptide of type I collagen (PICP) and N‐terminal propeptide of type III collagen (PIIINP), alkaline phosphatase (AP) and osteocalcin (OC) were measured at the start and after 2 and 12 weeks of periods of no treatment, GH 1·5 IU/m2 and GH 3·0 IU/m2. Twelve‐week washout periods were applied between the 12‐week GH‐treatment periods. High‐dose GH treatment was given during the second year of study and all serum markers were measured at start, after 2 and 12 weeks and 1 year of GH 6·0 IU/m2. In 18 non‐GH‐treated children with ISS the same parameters were measured yearly. The bone resorption marker urinary deoxypyridinoline (DPD) was measured during 12‐h day and night periods at start and after 2 weeks GH 1·5, 3·0 and 6·0 IU/m2.results  All markers were GH dependent, but the timing of maximal response varied among different markers. Height SDS at start, age at start and IGF‐II at baseline were inversely related to the first‐year growth response (r = −0·73, P = 0·001; r = −0·53, P = 0·03; and r = −0·53, P = 0·03, respectively). Some statistically significant correlations between biochemical responses on low GH doses (1·5 or 3·0 IU/m2) and second‐year growth response were found, but these showed no consistent pattern. However, all changes in IGF‐I SDS after GH 6·0 IU/m2 measured either after 2 or 12 weeks or 1 year correlated significantly with the second‐year growth response (r = 0·55, P = 0·02; r = 0·81, P = 0·001; and r = 0·86, P < 0·001, respectively). Baseline or GH‐stimulated levels of peripheral markers did not correlate with the growth response.conclusion  The individual capacity of IGF‐I generation after high‐dose GH treatment (6·0 IU/m2) determines the growth response on high‐dose GH treatment. Peripheral markers do not seem to play a role in growth prediction of children with ISS.
Growth failure in a child showing characteristics of Seckel syndrome: possible effects of IGF‐I and endogenous IGFBP‐3
Authors: Schmidt A. , Chakravarty A. , Brommer E. , Fenne B. D. , Siebler T. , De Meyts P. , Kiess W. 
Published: March 2003

SummarySeckel syndrome is an autosomal‐recessive disorder with a frequency of less than 1/10 000 births in which there are multiple malformations including severe short stature. We report on a patient with Seckel syndrome with a current body height of −7·5 SDS. Laboratory investigations at the age of 19 months revealed high levels of IGF‐I, IGF‐II and IGFBP‐3. These data suggested the existence of IGF‐I resistance possibly caused by impairment of the IGF‐I receptor (IGF‐IR) or altered IGFBPs. The purpose of this investigation was to examine whether the growth retardation in a Seckel syndrome patient is related to an alteration in the IGF system. Analysis of IGF‐IR mRNA of patient's and control fibroblasts by solution hybridization/RNase protection assay did not show differences of IGF‐IR transcript expression or size. Affinity crosslinking studies using [125I]‐IGF‐I showed normal‐sized IGF‐IR–ligand complexes. Mutation analysis of the complete coding regions of the IGF‐I and IGF‐IR genes showed no evidence of genetic alterations. Ligand blot analysis of IGFBPs secreted by the patient's fibroblasts showed stronger signals than control cells. Quantitative measurement of IGFBP‐3 in cell‐conditioned media was performed by radioimmunoassay (RIA) and revealed a sixfold increase when compared to control fibroblasts. We conclude that in this patient with Seckel syndrome and severe growth impairment IGF‐I resistance is possibly related to altered production of IGFBP‐3.
Postpartum recurrence of Graves’ hyperthyroidism can be prevented by the continuation of antithyroid drugs during pregnancy
Authors: Nakagawa Yoshinori , Mori Kouki , Hoshikawa Saeko , Yamamoto Makiko , Ito Sadayoshi , Yoshida Katsumi 
Published: March 2003

Summaryobjective Previous studies recommend the discontinuation of antithyroid drug (ATD) therapy during pregnancy in women with well‐controlled Graves’ hyperthyroidism (GH). In this study, we investigated whether this termination of ATD therapy during pregnancy is beneficial in terms of postpartum GH recurrence.design A nonrandomized, retrospective study.patients Sixty‐five pregnant GH patients treated with maintenance doses of ATDs were assigned into two groups: ATD therapy was discontinued before delivery in Group 1, but continued during pregnancy and after delivery in Group 2.measurements The prevalence of postpartum recurrence or exacerbation of GH within 1 year after delivery was examined. Serum T4, T3 TSH, and TSH receptor antibody levels were measured.results In Group 1, 70·8% (17/24) of patients suffered a recurrence of GH within 1 year after delivery. In contrast, a postpartum exacerbation of GH was observed in only 29% (12/41) of patients in Group 2 (P < 0·01). Both exacerbations and recurrences of GH appeared primarily within 4–6 months after delivery. Apparent neonatal hypothyroidism and malformations were not observed in the offspring of either group.conclusion Continuing antithyroid drug therapy throughout pregnancy prevents postpartum recurrence of Graves’ hyperthyroidism without resulting in neonatal hypothyroidism or malformations.
Increased incidence of parathyroid adenomas following X‐ray treatment of benign diseases in the cervical spine in adult patients
Authors: Rasmuson Torgny , Damber Lena , Johansson Lennart , Johansson Robert , Larsson Lars‐Gunnar 
Published: March 2003

SummaryObjective To determine whether or not exposure to ionizing radiation as an adult increases the risk of developing parathyroid adenomas.Design and Patients A cohort of 27 415 patients had received X‐ray treatment to palliate pain originating from arthrosis and spondylosis from 1950 to 1964. In a subcohort of 8144 patients the cervical spine was the target, or one of the targets for the treatment. With the technique used it could be assumed that, as a rule, the parathyroid glands had been included in the treated volume. Patients with parathyroid adenomas were obtained from the Swedish Cancer Register from 1958 to 1995. The standardized incidence ratio (SIR) was calculated.Results The number of person‐years at risk was 180 492 in the cohort exposed at the cervical spine, and 412 994 in the control cohort irradiated only at other sites. The calculated dose in the parathyroid region in the study cohort was about 1 Gy. The observed number of parathyroid adenomas in the study cohort was 22, and 24 in the control cohort. Expected numbers based on population data were 12·0 and 24·7, respectively, giving an SIR of 1·83 (95% CI 1·14–2·76) and 0·97 (CI 0·62–1·45), respectively. Mean age at exposure was 48·9 years (SD 10·2) and at diagnosis 71·5 years (SD 8·3). The time from exposure to diagnosis varied from 2 to 34 years (median 26 years). The excess relative risk was about 0·8 per Gy.Conclusion Exposure to ionizing radiation to the cervical spine in adult age seems to be associated with an increased risk of developing parathyroid adenomas.