bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parathyroid hormone gene polymorphisms in primary hyperparathyroidism
Authors: Kanzawa Michiko , Sugimoto Toshitsugu , Kobayashi Tatsuya , Kobayashi Akira , Chihara Kazuo 
Published: March 2003

OBJECTIVEGenetic contributions to bone mineral density (BMD) and bone turnover are well known. In the present study, we analysed the relationship between restriction fragment length polymorphisms of the PTH gene and the development of primary hyperparathyroidism (pHPT) as well as its severity.PATIENTSSeventy‐nine pHPT patients and 104 age‐matched healthy controls were analysed.DESIGN AND MEASUREMENTSPTH genotypes were determined by polymerase chain reaction and BstB I or Dra II restriction fragment length polymorphisms. The presence and absence of BstB I or Dra II restriction sites of the PTH gene were indicated by B and b or D and d, respectively. BMD levels at the lumbar spine and at the radius were measured in all subjects. Serum levels of calcium, phosphorus, alkaline phosphatase and intact PTH were measured in pHPT patients.RESULTSThere were no differences in the frequencies of these PTH genotypes between pHPT patients and controls. In control subjects, lumbar BMD was significantly higher in BB genotype than in Bb/bb genotypes. In pHPT patients, there was no difference of BMD between BB and Bb/bb genotypes. In pHPT patients, serum calcium level was significantly higher in those with the BB genotype than Bb/bb genotypes. On the other hand, there was no association between DraII polymorphism and BMD in both controls and pHPT patients, but serum intact PTH level was significantly higher in DD genotype than Dd/dd genotype in pHPT patients. Moreover, serum levels of ALP and intact PTH were significantly higher in the PTH BBDD haplotype, compared to those in haplotypes other than BBDD.CONCLUSIONSThe present study suggests that the BstB I polymorphism of PTH gene is closely related to bone mineral density and that PTH gene polymorphisms do not seem to affect the development of primary hyperparathyroidism but may relate to the severity of primary hyperparathyroidism.
GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety
Authors: Abs Roger , Bengtsson Bengt‐Åke , Hernberg‐Ståhl Elizabeth , Monson John P. , Tauber Jean‐Pierre , Wilton Patrick , Wüster Christian 
Published: March 2003

OBJECTIVELong‐term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long‐term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting.PATIENTSThe present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years.RESULTSPrior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease‐specific questionnaire (QoL‐AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non‐naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF‐I indicated that overtreatment with GH was markedly more common in non‐naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment.CONCLUSIONSOur data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well‐tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.
Acidic isoforms of chorionic gonadotrophin in European and Samoan women are associated with hyperemesis gravidarum and may be thyrotrophic
Authors: Jordan Vanessa , Grebe Stefan K. G. , Cooke Russell R. , Ford Henry C. , Larsen Peter D. , Stone Peter R. , Salmond Clare E. 
Published: March 2003

OBJECTIVEThere is conflicting evidence concerning the role of human chorionic gonadotrophin (hCG) in the aetiology of hyperemesis gravidarum (HG); particular isoforms of hCG may be the critical factor. Ethnic differences in HG prevalence and putative thyrotrophic effects of hCG may also relate to differences in hCG isoform profiles. To address these issues we examined the relationship of hCG isoforms to HG and thyroid function tests in two groups of women from ethnic backgrounds with significantly different HG prevalence rates.PATIENTS AND DESIGNWe enrolled 10 European and 10 Samoan women with HG and an equally sized non‐hyperemetic, gestational stage matched control group.MEASUREMENTSWe administered a questionnaire, generated serum hCG charge‐isoform profiles by chromatofocusing and measured the serum concentrations of total hCG, oestradiol (E2), thyrotrophin (TSH) and free thyroxine (FT4).RESULTSThe mean serum total hCG levels were highest in the Samoan hyperemetics (176 268 IU/l), and overall higher in hyperemetics compared with controls (159 770 IU/l vs. 86 420 IU/l, P < 0.001). When compared with controls, hyperemetics displayed increased hCG concentrations in the more acidic half (pH < 4) of the chromatofocusing pH range (89 843 IU/l vs. 41 146 IU/l, P < 0.003). Serum E2 levels did not differ between the four groups, but correlated with the hCG concentration between pH 5.2 and 4.01. Mean serum TSH levels were significantly lower in hyperemetics than in controls (0.33 mIU/l vs. 1.19 mIU/l, P < 0.001) and correlated with the hCG concentration between pH 4.6 and 2.8, while serum FT4 correlated with the hCG concentration below pH 4.0.CONCLUSIONSAcidic isoforms of hCG may play a role in the aetiology of HG and gestational thyrotoxicosis. Minor ethnic differences in hCG isoform profiles were observed, but the relationship of acidic hCG isoforms to HG and serum thyroid hormone levels was largely independent of the patients' ethnicity. The mechanisms by which acidic isoforms might provoke nausea remain uncertain, but do not seem to involve E2, while the longer half‐life of acidic hCG isoforms may result in increased in vivo TSH receptor cross‐talk with resultant thyrotrophic effects.
Reduced foetal growth and growth hormone secretion in adult life
Authors: Flanagan Daniel E , Moore Vivienne M , Godsland Ian F , Cockington Richard A , Robinson Jeffrey S , Phillips David I W 
Published: March 2003

OBJECTIVESRecent studies suggest that growth restriction or other adverse influences acting in utero or during early infancy lead to permanent alterations in growth hormone (GH) secretion. As GH secretion is known to predict cardiovascular risk, alterations in GH may contribute to the association between reduced foetal growth and cardiovascular disease. We have therefore assessed the relationship between birth size and GH secretion in a prospective study of young adults whose birth size was recorded and who have had their current blood pressure and glucose tolerance measured.DESIGNProspective cohort studyPATIENTS153 healthy men and women, aged 20–21 years.MEASUREMENTSSubjects carried out a timed overnight urinary collection for analysis of GH excretion. Insulin sensitivity and insulin secretion were measured using the intravenous glucose tolerance test with minimal model analysis. Blood pressure, height, weight, usual level of exercise, smoking habits, alcohol consumption, and socio‐economic status were also recorded.RESULTSGH excretion ranged from 0.01 to 41.8 μU per subject. It did not differ according to gender but was markedly reduced in obese subjects (P < 0.0001) Low birthweight was strongly associated with low GH excretion at age 20 years (P = 0.002). Low placental weight and short body length also predicted low GH (P = 0.02 and P = 0.04, respectively). These relationships were independent of other confounding factors including obesity. GH excretion was not independently related to current levels of blood pressure, insulin sensitivity or insulin secretion.CONCLUSIONSBody size at birth predicts GH excretion in adult life. Low GH excretion in people who were small at birth may be one mechanism explaining their increased risk of cardiovascular disease.
Type 1 multiple endocrine neoplasia (MEN1): contribution of genetic analysis to the screening and follow‐up of a large French kindred
Authors: Waterlot  , Porchet  , Bauters  , Decoulx  , Wémeau  , Proye  , Degand  , Aubert  , Cortet  , Dewailly  
Published: March 2003

OBJECTIVEMultiple endocrine neoplasia type 1 (MEN1) is an autosomal genetic disorder, the clinical phenotype of which includes tumours of the parathyroids and/or anterior pituitary and/or endocrine pancreas. The genetic defect has been mapped to the chromosome 11q13 and the MEN1 gene has been recently identified, thus allowing genetic screening in affected kindreds. The aim of this study was to establish the usefulness of genetic screening in the follow‐up of a large MEN1 kindred.PATIENTSWe describe a large kindred of 91 members, of whom 56 had clinical, biochemical and genetic screening. Twenty eight of them have been tested annually for the last 5 years.RESULTSAlthough the precise mutation is still undetermined in this kindred, genotypic determination confirmed linkage with the MEN1 gene in affected members and excluded 28 members from annual testing. By drawing our attention to susceptible subjects, genetic screening improved the evaluation of age‐related penetrance of the disease in the 3 generations from this kindred. For instance, annual screening showed conversion from unaffected to affected phenotype in 4 subjects aged 14, 14, 15, and 17 years. Moreover, genetics helped us to evaluate the specificity of clinical or biochemical markers, and thus to discard useless investigations. So far however, the genetics have not helped to explain the phenotypic heterogeneity and particularly low incidence of pancreatic tumours in this kindred.CONCLUSIONGenetic screening is very useful in detecting high risk individuals for MEN 1, since it avoids time‐consuming and expensive investigations in non‐affected subjects. By providing better understanding of the age‐related penetrance of this syndrome, it improves the efficiency of screening. Genetic studies allow differentiation between clinical and biochemical features that are useful in follow‐up and other confusing or unhelpful parameters.
Extrusion of testosterone pellets: a randomized controlled clinical study
Authors: Kelleher  , Turner  , Howe  , Conway  , Handelsman  
Published: March 2003

BACKGROUNDIt has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side‐effect. The present study aimed to reduce the extrusion rate.OBJECTIVETo determine whether the washing of testosterone pellets to remove potentially surface‐adherent particles decreased the rate of extrusion of pellet implants.DESIGNProspective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group.PATIENTSThe study included 251 testosterone implantation procedures in men with known androgen deficiency.MEASUREMENTSThe primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end‐points included peri‐procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow‐up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors.RESULTSIn the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1.09 [95% CI 0.47–2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44–3.9], bleeding/bruising (8.8%, 1.23 [0.47–3.3]) and infection (4.0%, 1.54 [0.35–7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77).CONCLUSIONSThe pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow‐up or a secular trend.
Thyroid suppression test with L‐thyroxine and [99mTc] pertechnetate
Authors: Ratnos Celso D. , Zantut‐Wittmann Denise E. , Tambascia Marcos A. , Assumpção Lígia , Etchebehere Elba C. S. C. , Camargo Edwaldo E. 
Published: March 2003

SummaryOBJECTIVE The thyroid suppression test is still used in some centres as an adjunt in the diagnosls of autonomous functioning thyroid nodules. With the purpose of minimizing the disadvantages of the original T3 suppression test, we have evaluated the efficacy of a method using L‐thyroxine as TSH suppression agent and [99mTc] pertechnetate as radio‐pharmaceutical.DESIGN Open nonrandomized prospective study MATERIALS AND METHODS A control group of 15 normal volunteers (11 males, 4 females; 21–35 years, mean 26–4 years) and a patient group of 20 patients (18 females, 2 males: 27–83 years, mean 53.6 years) divided into 4 subgroups, were studied: 7 patients with autonomous functioning nontoxic nodules, 3 with autonomous functioning toxic nodules, 7 with Graves disease and 3 with nonautoimmune diffuse toxic goitre. Baseline thyroid uptake and imaging were begun 20 minutes after an intravenous injection of 370 MBq (10mCi) of [99mTc] pertechnetate. This was followed by a single daily intake of 2μg/kg of L‐thyroxine, for 10 days. Thyroid imaging and uptake were then repeated.RESULTS In the control group [99mTc] pertechnetate uptake after L‐thyroxine suppression had a mean reduction of 75.8 ± 7.69% (58–47%) in comparison to the baseline level. All subjects were euthyroid by clinical and laboratory criteria and none complained of side‐effects, despite significant suppression of TSH levels. In the patient group, thyroid uptake after suppression decreased in 10 patients (maximum reduction 39%), was unchanged In 2 patients and increased in the remaining 8 patients. CONCLUSION The method described was efficient for demonstration of autonomous thyroid tissue, since none of the patients showed significant reduction of thyroid uptake after L‐thyroxine suppression compared with the control group. This test was as effective as the original T3 suppression test, but more convenient to the patient: no side‐effects, ease of hormonal intake, low dosimetry and short stay in the nuclear medicine laboratory.
Analysis of the peroxisome proliferator activated receptor γ (PPARγ) gene in HAIRAN syndrome with obesity
Authors: Globerman H. , Zauberman Y. , Makarov T. , Beamer B. A. , Yen C‐J. , Shuldiner A. R. , Harel C. , Karnieli E. 
Published: March 2003

SummaryOBJECTIVES To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor γ (PPARγ), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARγ and the degree of insulin resistance.DESIGN A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non‐diabetic non‐obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non‐diabetic non‐obese individuals. MEASUREMENTS Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARγ isoforms (PPARγ1 and PPARγ2) for single‐stranded conforma‐tional polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS A synonymous substitution in codon 477 (CACHis← CAFHis) was found in one patient. A missense mutation in codon 12 of PPARγ2 (CCApro← GCAAla) was found in another patient, but not in any of 25 non‐diabetic, non‐obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS Mutations in the PPARγ gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.
Vitamin D receptor gene start codon polymorphism (FokI) and bone mineral density in healthy male subjects
Authors: Kanan R. M. , Varanasi S. S. , Francis R. M. , Parker L. , Datta H. K. 
Published: March 2003

OBJECTIVEThe genetic factors determining peak bone mineral density (BMD) in men are not well characterized. Recent studies have investigated the relationship between the start codon polymorphism (SCP) of the vitamin D receptor (VDR) gene and BMD in different populations. We have now examined the relationship between SCP of the VDR gene and BMD in a group of healthy Caucasian men from the north‐east of England.SUBJECTSNinety‐six healthy men (median age 50, range 40.0–77.0 years).MEASUREMENTSAnalysis of the FokI genotypes of SCP of the VDR and measurements of BMD at the femoral neck and lumbar spine were performed.RESULTSFF, Ff and ff VDR FokI genotypes were found to have the highest, intermediate and the lowest lumbar spine BMD, respectively (Mean ± SD, for FF 1.07 ± 0.14, Ff 1.05 ± 0.16 and ff 0.95 ± 0.10 g/cm2). There was a significant difference in spine BMD between FF and ff genotypes (P < 0.05, analysis of variance [anova]), but no such difference was apparent between Ff and ff (P > 0.05, anova). Interestingly, there was no association between FokI polymorphism and femoral neck BMD (Mean ± SD, for FF 0.85 ± 0.12, Ff 0.87 ± 0.15 and ff 0.83 ± 0.15 g/cm2). The distribution of FokI VDR genotypes approached Hardy–Weinberg equilibrium and was similar to that reported for women from different ethnic groups, as the prevalence of FF and ff genotypes was 44% and 16%, respectively.CONCLUSIONThe study shows that in this population of healthy men there is a weak association between lumbar spine bone mineral density and FokI restriction fragment length polymorphism at the translation initiation site of the vitamin D receptor gene.
Reduced vitamin D receptor expression in parathyroid adenomas: implications for pathogenesis
Authors: Sudhaker Rao  , Han  , Phillips Evelyn R. , Palnitkar Saroj , Parfitt  
Published: March 2003

BACKGROUND AND OBJECTIVESParathyroid adenomas discovered fortuitously grow very slowly and their cell birth rate greatly declines, features explicable by an initial increase in secretory set‐point. In the nodules of severe uraemic parathyroid hyperplasia, there is an increased set‐point and decreased expression of both the calcium sensing receptor (CaSR) and the vitamin D receptor (VDR). Accordingly, we examined VDR and CaSR expression in parathyroid adenomas.PATIENTS AND DESIGNWe studied 24 patients with primary hyperparathyroidism with a wide range of vitamin D nutritional status (plasma 25‐hydroxyvitamin D range 10–107 nmol/l). Eighteen patients discovered by biochemical screening were enrolled in a natural history or treatment option study, and six additional US patients matched a group studied concurrently in India with low plasma 25‐hydroxyvitamin D level (< 37 nmol/l).MEASUREMENTSReceptor expression was determined by immunocytochemistry in each tumour and in 11 cases also in adjacent nonadenomatous tissue. VDR expression was reported as the proportion of positive cells (strongly rather than weakly stained) determined by systematic random sampling and CaSR expression as grey scale values of staining intensity in arbitrary units determined by image analysis.RESULTSThe mean (SD) proportion of cells positive for VDR was 2.93 (2.17)% in the parathyroid adenomas and 95.7 (5.10)% in the nonadenomatous tissue. In about two‐thirds of the cases VDR positive cells could have been remnants of a normal gland, but in the remaining one‐third they were too numerous to be accounted for by this explanation. The mean (SD) intensity of CaSR expression was 151 (4.71) units in parathyroid adenomas and 218 (5.0) units in nonadenomatous tissue (P < 0.001). The frequency of VDR loss and the changes in CaSR immunohistochemistry were unrelated to race, sex, or disease severity, except that the reduction in CaSR was significantly greater in patients with normal vitamin D nutrition (32.1% vs. 29.0%).CONCLUSIONS(1) There is reduction of vitamin D receptor expression in almost all cells in parathyroid adenomas. This defect was probably present in the founder cell of the tumour clone in the majority of cases. Since mutations in the vitamin D receptor gene have been sought but not found, possible explanations include inhibition of vitamin D receptor gene transcription, decreased amount of the corresponding mRNA, or failure of normal translation. (2) Reduction in calcium sensing receptor could be either the primary defect or (more commonly) secondary to loss of vitamin D receptor and is of sufficient magnitude to account for the increase in secretory set‐point and consequent asymptotic growth and stable clinical course.