bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of somatic mutation in determining the affinity of anti-DNA antibodies
Authors: BEHRENDT M , PARTRIDGE L J , GRIFFITHS B , GOODFIELD M , SNAITH M , LINDSEY N J 
Published: March 2003

SUMMARY
Combinatorial antibody libraries were constructed from the spleen of a patient with concomitant systemic lupus erythematosus and idiopathic thrombocytopenia. Following selection of the libraries with DNA, a panel of 15 anti-DNA Fabs was isolated. Sequence analysis of these antibodies coupled with measurements of their affinities for ss- and dsDNA were used to investigate the role of somatic mutation in affinity maturation of the anti-DNA response. Examination of the germline genes used by these Fabs supports previous studies that suggest there is no restriction of the gene usage in the anti-DNA response. However, data are presented indicating that VH3 genes and the A27 V paired with the J1 may be over-expressed in the anti-DNA repertoire. Analysis of the role of somatic mutation in increasing affinity for DNA indicates that affinity maturation has occurred and suggests that the CDR1 and CDR2 of the heavy chain are of importance in this process.
Xenobiotic metal-induced autoimmunity: mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice
Authors: HANSSON M , ABEDI-VALUGERDI M 
Published: March 2003

SummaryXenobiotic-metals such as mercury (Hg) and silver (Ag) induce an H-2 linked antinucleolar autoantibody (ANolA) production in susceptible mice. The mechanism for induction of ANolA synthesis is not well understood. However, it has been suggested that both metals interact with nucleolar proteins and reveal cryptic self-peptides to nontolerant autoreactive T cells, which in turn stimulate specific autoreactive B cells. In this study, we considered this suggestion and asked if mercury and silver display, if not identical, similar cryptic self-peptides, they would induce comparable ANolA responses in H-2 susceptible mice. We analysed the development of ANolA production in mercury- and/or silver-treated mice of H-2s, H-2q and H-2f genotypes. We found that while mercury stimulated ANolA synthesis in all strains tested, silver induced ANolA responses of lower magnitudes in only H-2s and H-2q mice, but not in H-2f mice. Resistance to silver in H-2f mice was independent of the dosage/time-period of silver-treatment and non-H-2 genes. Further studies showed that F1 hybrid crosses between silver-susceptible A.SW (H-2s) and -resistant A.CA (H-2f) mice were resistant to silver, but not mercury with regard to ANolA production. Additionally, the magnitudes of mercury-induced ANolA responses in the F1 hybrids were lower than those of their parental strains. The above differential ANolA responses to mercury and silver can be explained by various factors, including the different display of nucleolar cryptic peptides by these xenobiotics, determinant capture and coexistence of different MHC molecules. Our findings also suggest that the ability of a xenobiotic metal merely to create cryptic self-peptides may not be sufficient for the induction of an ANolA response.
Serum free IGF‐I, total IGF‐I, IGFBP‐1 and IGFBP‐3 levels in an elderly population: relation to age and sex steroid levels
Authors: Janssen  , Stolk  , Pols  , Grobbee  , De Jong  , Lamberts  
Published: March 2003

BACKGROUNDMost previous studies concerning the relationship between IGF‐I and age used assays measuring total IGF‐I. Although free IGF‐I is considered of greater biological relevance, little is known about its relationship with sex steroids levels in elderly healthy subjects.MEASUREMENTSIn a cross‐sectional study of 218 healthy people (103 men, 115 women) aged 55–80 years we measured serum total and free IGF‐I, IGFBP‐1 and IGFBP3 levels and sex steroids. Free androgen index and free oestradiol index were used as an indicator for free oestradiol and free testosterone levels, respectively.RESULTSFree IGF‐I levels did not decline with age in the whole study population. Free IGF‐I levels even increased in individuals above 70 years of age in comparison to those aged between 55 and 70 years (mean ± SE 0.106 ± 0.007 nmol/l vs. 0.086 ± 0.004 nmol/l, P = 0.009). Total IGF‐I and IGFBP‐3 decreased with age (r = −0.20, P = 0.005 and r = −0.24, P = 0.001, respectively). Total IGF‐I levels were positively related with free oestrogen index in both sexes. Free IGF‐I did not relate to free oestrogen or androgen index. In women only, free IGF‐I was related positively with DHEAS while IGFBP‐1 was inversely correlated with DHEAS.CONCLUSIONSFree IGF‐I levels do not decrease with age and are even higher in individuals above 70 years. There was no relationship between free IGF‐I and free androgen or oestrogen index in either gender. We hypothesize that higher free IGF‐I levels in older persons may be the consequence of selective survival in the cohort: subjects with high free IGF‐I levels may live longer. The absence of a relationship between free IGF‐I levels and free androgen and oestrogen indices suggests that there is no direct interaction between the biological activity of circulating IGF‐I levels and sex hormone production in a healthy ageing population.
Retinoid X receptor expression in the normal pituitary and clinically ‘non‐functioning’ pituitary tumours
Authors: Gittoes  , McCabe  , Verhaeg  , Sheppard  , Franklyn  
Published: March 2003

OBJECTIVEThe glycoprotein hormone common α‐subunit is frequently expressed in clinically ‘non‐functioning’ tumours (NFTs) of the anterior pituitary, despite normal levels of T3 and gonadal steroids. This observation suggests abnormal negative‐feedback regulation of the α‐subunit by T3 and gonadal steroids in NFTs. We have previously documented reduced expression of thyroid hormone receptor (TR) variants in NFTs compared to normals and proposed that this observation may, in part, explain the defective negative regulation. Due to the important role of retinoid X receptors (RXRs) in transactivating TR‐mediated transcriptional regulation, via heterodimer formation, we hypothesize that aberrant RXR isoform expression in NFTs may contribute to the defective negative regulation of the α‐subunit by T3.DESIGNComparison of RXR isoform protein and mRNA expression in NFTs and normal pituitaries.PATIENTS AND TUMOURSTwenty clinically non‐functioning pituitary tumours and 27 normal pituitaries were obtained for analysis.MEASUREMENTSImmunocytochemistry and semiquantitative RT‐PCR was performed on tumours and normal pituitaries to determine the relative levels of expression of RXR isoform proteins and mRNAs, respectively.RESULTSRXRα was expressed in a similar proportion (approximately 50%) of both normal human pituitaries and NFTs, while RXRβ and γ were each observed in 26% of normals but were undetectable in NFTs. The application of semiquantitative RT‐PCR revealed similar levels of mRNAs encoding the RXRα and RXRβ isoforms in normals and NFTs but significantly reduced expression of RXRγ mRNA was observed in NFTs.CONCLUSIONSWe propose that abnormal RXR isoform expression in clinically ‘non‐functioning’ pituitary tumours may contribute to abnormal T3‐mediated negative regulation of α‐subunit production.
Serum leptin concentrations in patients with thyroid disorders
Authors: Yoshida Tadashi , Momotani Naoko , Hayashi Matsuhiko , Monkawa Toshiaki , Ito Kunihiko , Saruta Takao 
Published: March 2003

OBJECTIVELeptin, the obese gene product, is secreted exclusively by adipocytes and is thought to act as a lipostatic signal that regulates body weight homeostasis. We previously reported that thyroid hormone is one of the up‐regulating factors of leptin in vitro. T3, at physiological concentrations, stimulates leptin mRNA expression and leptin secretion by 3T3‐L1 adipocytes. The aim of this study was to explore the role of thyroid hormone in the regulation of leptin in humans.DESIGN AND PATIENTSA total of 59 non‐obese women aged 38.4 ± 1.8 years (mean ± SEM) were studied: 19 patients with hyperthyroidism, 17 patients with hypothyroidism, and 23 normal control subjects. The correlation between serum leptin concentrations and body mass index (BMI) was analyzed, and serum leptin levels were compared among the three groups.MEASUREMENTSSerum leptin concentrations were measured by radioimmunoassay.RESULTSSerum leptin concentrations after logarithmic transformation were correlated significantly (P < 0.05) with BMI in the hyperthyroid (r = 0.46), the hypothyroid (r = 0.84), and normal (r = 0.63) groups. Even though age, body weight, and BMI were similar in all groups, serum leptin levels in the hypothyroid patients (5.30 ± 1.12 μg/l) were significantly (P < 0.05) lower than in the hyperthyroid and normal groups (6.87 ± 0.66 and 6.58 ± 0.68 μg/l, respectively).CONCLUSIONSThese results indicate that thyroid hormone may play an important role in the appropriate secretion of leptin in humans.
Inhibin A and inhibin B in women with polycystic ovarian syndrome during treatment with FSH to induce mono‐ovulation
Authors: Anderson R. A. , Groome N. P. , Baird D. T. 
Published: March 2003

OBJECTIVEPolycystic ovary syndrome (PCOS) is characterized by the presence of numerous small antral follicles arrested at a diameter of less than 10 mm. As development of large antral follicle(s) can be stimulated by the administration of FSH, it has been suggested that the arrest of follicle development is due to a relative lack of or resistance to FSH. We have measured the concentration of FSH and LH and the ovarian hormones oestradiol, inhibin A and B, in relation to the dynamics of follicular development in women with PCOS under basal conditions and during treatment with FSH.DESIGNThe concentrations of FSH, LH, oestradiol, inhibin A and B were measured in women with PCOS who were untreated (n = 9) or following progesterone‐induced menses (10 cycles in six women) and control women on day 3 of a normal cycle (n = 10). Serial measurements of the same hormones were made during induction of ovulation with low dose of exogenous FSH in the women with PCOS who had been treated with progesterone. The dynamics of follicle development were measured by serial pelvic ultrasound examinations during treatment with FSH in PCOS and in the follicular phase of control cycles.PATIENTSNine anovulatory untreated women with PCOS were compared with 10 normal women and six women with PCOS undergoing FSH treatment.RESULTSThe concentrations of inhibin B and LH were higher in both groups of women with PCOS than in normal control women on day 3. In untreated women with PCOS the concentration of inhibin A was also significantly elevated compared to control women (P < 0.01) but not in women pretreated with progesterone. Basal concentrations of oestradiol were also significantly higher in women with PCOS than in the early follicular phase of the normal cycle. There were no significant differences in the concentration of FSH between the groups. Treatment of women with PCOS with low doses of FSH stimulated the development of a single dominant follicle which had an identical rate of growth and secretion of oestradiol and inhibin A to that observed in spontaneous cycles in normal women. In contrast to normal women, the concentration of inhibin B rose 7‐fold following FSH treatment and remained elevated until the luteal phase.CONCLUSIONSThe raised concentrations of inhibin A and B in women with PCOS probably reflects the increased number of small antral follicles characteristically present in that condition. The striking similarity in the dynamics of growth of the dominant follicle and the pattern in concentration of oestradiol and inhibin A in normal women and in women with PCOS treated with modest amounts of FSH, suggests that the arrest of follicle development in PCOS may be due to a relative deficiency of FSH which may in turn be secondary to increased secretion of either or both inhibin forms.
Effects of chronic opioid antagonism on gonadotrophin and ovarian sex steroid secretion during the luteal phase
Authors: Rossmanith Winifried G. , Monn Marcel , Benz Reiner 
Published: March 2003

OBJECTIVESSince short‐term opioid antagonism increases LH pulsatility during the luteal phase in women, we postulated that prolonged opioid antagonism may also accelerate the LH secretory episodes at this time. If so, the functional and temporal links between secretory episodes of pituitary LH and oestradiol (E2) and progesterone (P) release from the mature human corpus luteum may be disrupted.STUDY DESIGNProlonged opioid blockade with the oral antagonist naltrexone (100 mg daily) was effected in eight women during the entire luteal phase of their cycles. Following documented ovulation in both placebo (control) and naltrexone cycles, blood samples were obtained daily and frequently (every 10 minutes for 10 h) on days 6–8 after ovulation.MEASUREMENTSIn all blood samples, LH, E2 and P were determined by IRMA.RESULTSCompared to control cycles, the temporal organization and the endocrine characteristics of the luteal phase remained virtually unchanged during chronic opioid blockade. Periodic fluctuations were detected (by cluster analysis) in LH, E2 and P data series established by frequent sample collections in both the control and naltrexone cycles. LH secretory profiles were remarkably similar during control and naltrexone cycles, and the E2 and P secretory episodes tended to be coupled to LH pulses during both cycles. As determined by time–series analysis, the cross‐correlations between the LH/E2 and LH/P data series remained unaltered by opioid blockade.CONCLUSIONSChronic opioid antagonism with naltrexone did not disrupt the temporal organization or endocrine characteristics of the luteal phase. In particular, prolonged opioid blockade did not change LH secretory patterns. The functional and temporal links between LH inputs and sex steroid release from the mature corpus luteum remained unaffected by prolonged opioid antagonism. In contrast to the effects of short‐term opioid blockade on LH pulsatile release during the luteal phase, the effects of chronic opioid antagonism on LH release may be transient and may not persist throughout the entire luteal phase, suggesting desensitization of the opiate receptors.
Calcitonin deficiency in early stages of chronic autoimmune thyroiditis
Authors: Borges Maria F. , Abelin Neusa M. A. , Menezes Fernanda O. M. , Dahia Patricia L. M. , Toledo Sergio P. A. 
Published: March 2003

OBJECTIVESAlthough calcitonin (Ct) deficiency has been described in chronic autoimmune thyroiditis (CAT) it is unclear at what stage in the disease it develops. We have analysed the Ct secretory responses of patients in two different evolutionary stages of CAT, namely the goitrous and atrophic phases.DESIGNWe studied the Ct response to combined calcium (2 mg/kg) and pentagastrin (0.5 μg/kg) intravenous infusion in 27 patients with CAT and 30 normal adult controls. The cases were divided into two groups. The first comprised eleven women with CAT and goitrous subclinical hypothyroidism (GH), aged 28.6 ± 10.1 years—at diagnosis they had increased thyroid autoantibody titres and cytological features compatible with stages 1 and 2 of Hashimoto's thyroiditis. The second comprised 16 females with CAT and an atrophic thyroid confirmed by ultrasound scan, aged 38.0 ± 9.2 years—these patients were severely hypothyroid at diagnosis and were termed AH (atrophic hypothyroidism). Both groups (GH and AH) received replacement doses of thyroxine sufficient to restore euthyroidism for at least six months before the stimulation tests. Control group (C) consisted of 20 healthy women (A), aged 30.0 ± 9.6 years, and 10 healthy men (B), aged 34.7 ± 8.0 years. Serum Ct was measured by IRMA. The Ct secretory response was related to thyroid size and cytological data, when available.RESULTSBasal Ct concentrations in groups GH (0.08 ng/l, median) and AH (0.07 ng/l, median) were significantly lower than those of female controls (0.58 ng/l, median). Stimulated Ct peak values in groups GH (0.08 ng/l, median) and AH (0.19 ng/l, median) were significantly lower than those of female controls (13.61 ng/l, median). Also, both basal (2.72 ng/l, median) and stimulated Ct levels (35.73 ng/l, median) in male controls were significantly higher than in female controls given already. A positive correlation between the Ct secretory reserve and thyroid dimensions, evaluated by ultrasound scan, was found only in patients with thyroid atrophy (AH; rs = 0.61,P < 0.05).CONCLUSIONSWe have found low basal and stimulated calcitonin values in patients with chronic autoimmune thyroiditis and thyroid enlargement, which represents an early phase of chronic autoimmune thyroiditis. Our data have also confirmed previous findings of deficient calcitonin secretion in advanced stages of chronic autoimmune thyroditis in which thyroid atrophy is usually found. These findings may be associated with C‐cell destruction following progressive, nonspecific follicular cell damage caused by lymphocytic infiltration and fibrosis of the gland.
Effect of long‐term growth hormone treatment on carbohydrate metabolism in children with growth hormone deficiency
Authors: Seminara Salvatore , Merello Giovanna , Masi Stefano , Filpo Antonio , La Cauza Francesca , D'Onghia Giovanna , Martelli Elena , Loche Sandro 
Published: March 2003

OBJECTIVEGrowth hormone (GH) has well known effects on carbohydrate metabolism. We have evaluated the effects of long‐term growth hormone (GH) therapy on carbohydrate metabolism in children with classical GH deficiency (GHD) or GH neurosecretory dysfunction (GHND)STUDY DESIGNGlucose, insulin and C‐peptide concentrations at baseline and during oral glucose tolerance test (OGTT) were measured before and after 18 and 36 months of GH therapy (0.6–0.8 IU/Kg/week in 6 evening doses) in 13 GHD and 7 GHND children (15 boys and 5 girls, 15 prepubertal and 5 early pubertal; age at diagnosis 2.11–13.1 y).RESULTSMean fasting insulin and C‐peptide concentrations after 18 months were similar to the pretreatment values, while after 36 months they were significantly higher than before treatment. Fasting glucose concentrations were similar to pretreatment both after 18 and 36 months. The mean areas under the curve (AUC) during OGTT for glucose, insulin, and C‐peptide were significantly increased after 18 and 36 months. There were no differences between GHD and GHND patients. During the treatment period 10 of the 15 prepubertal patients entered puberty. A significant increase of insulin and C‐peptide concentrations occurred after 36 months of GH treatment in the patients that remained prepubertal during treatment as well as in those who were pubertal when treatment was started. In three of our patients GH treatment caused glucose intolerance, which resolved after 6–12 months of a normal calorie low‐simple carbohydrate diet without requiring discontinuation of treatment.CONCLUSIONOur data show that long‐term GH treatment in GH deficient children causes hyperglycaemia and increased insulin secretion. These effects may in some patients induce glucose intolerance, which is reversible with appropriate dietary measures and does not require discontinuation of treatment.
Characterization of serum SHBG isoforms in prepubertal and pubertal girls
Authors: Bedecarrás  , Gryngarten  , Ayuso  , Escobar  , Bergadá  , Campo  
Published: March 2003

OBJECTIVESHBG is a circulating glycoprotein that binds dihydrotestosterone, testosterone and oestradiol with high affinity and low capacity. In girls, serum concentrations of SHBG gradually decrease with age due to a true fall in concentration and not to a change in the binding characteristics. The aim of our study was to determine the pattern of serum SHBG isoforms in normal girls in early childhood (ECh), late childhood (LCh) and puberty (P).SUBJECTSFifteen normal girls were studied. They were divided into three groups according to their age: ECh: 3.7 ± 0.9 years (mean ± SD, n = 5); LCh: 6.4 ± 0.5 years (n = 5); and P: 13.4 ± 1.5 years (n = 5).METHODS AND MEASUREMENTSPreparative isoelectric focusing was used to isolate SHBG isoforms according to their isoelectric point (pI).Three groups of isoforms were isolated: SI: pI 5.2–5.4; SII: pI 5.4–5.6 and SIII: pI 5.6–5.8. Steroid levels in serum were determined by RIA.RESULTSThe relative distribution of SHBG isoforms (% of the total SHBG recovered, mean ± SD) in the three groups of girls studied was: ECh: SI: 25.8 ± 9.9, SII: 53 ± 10.5 and SIII: 21.2 ± 1.6; LCh: SI: 8.8 ± 3.1, SII: 58.8 ± 12.2 and SIII: 31.8 ± 8.6; P: SI: non‐detectable; SII: 51.6 ± 12.6 and SIII: 48.4 ± 12.6.CONCLUSIONThese results indicate that serum SHBG is more heterogeneous before puberty. A considerable proportion of acidic isoforms are present early in life; they decrease during the prepubertal period and disappear when sexual development is completed. After puberty the glycoprotein is more homogeneous and an important proportion of more basic isoforms is present. At puberty serum SHBG not only falls in concentration but also has an altered sialic acid content which modulates its circulating half‐life.
Screening for primary aldosteronism with a logistic multivariate discriminant analysis*
Authors: Rossi Gian Paolo , Rossi Ermanno , Pavan Edoardo , Rosati Nicoletta , Zecchel Roberto , Semplicini Andrea , Perazzoli Franco , Pessina Achille C. 
Published: March 2003

OBJECTIVEPrimary aldosteronism (PA) is the most common endocrine cause of curable hypertension, but no single test unequivocally identifies it. Accordingly, we investigated the usefulness of a logistic multivariate discriminant analysis (MDA) approach for PA screening.DESIGNGeneration of a logistic MDA function based on retrospective analysis of biochemical tests in a large cohort of referred patients with/without confirmed Conn's adenoma (CA), followed by prospective validation of the model.PATIENTSWe investigated 574 selected hypertensives: 206 (32 with and 174 without CA) retrospectively, 48 (with a 13% prevalence of CA) prospectively for the validation of the model, and 320 referred hypertensives (with a 3.4% prevalence of CA) similarly evaluated. Patients were referred to a specialised centre for hypertension (4th Clinica Medica—University of Padua) and to a department of Internal Medicine of a regional hospital (Reggio Emilia).MEASUREMENTSIn all patients we measured several demographic and biochemical variables and performed a captopril test. A stepwise analysis of variance, based on a model fitted with several different variables, identified baseline (sALDO) and captopril‐suppressed plasma aldosterone (cALDO), supine plasma renin activity (sPRA) and K+ as the most informative. Therefore, two models of logistic MDA with sPRA, K+, and either sALDO (model A) or cALDO (model B) were developed and used. ROC analysis was also performed to assess the optimal cut‐off values.RESULTSThe model B of MDA provided the best performance and identified CA with 100% sensitivity and 81% accuracy. When used prospectively it showed 100% sensitivity, both in the Padua (88% accuracy) and in the Reggio Emilia series (90% accuracy). However, at both institutions most patients with idiopathic hyperaldosteronism (IHA) were also detected.CONCLUSIONSThus, although developed from patients with confirmed Conn's adenoma, a strategy based on multivariate discriminant analysis can be used prospectively for accurate screening for primary aldosteronism. Furthermore, it was proven to be accurate and applicable to patients tested with similar modalities at a different institution. Although this approach did not provide a clear‐cut discrimination of Conn's adenoma from idiopathic hyperaldosteronism, it may avoid unnecessary and costly further testing in patients with a low probability of primary aldosteronism.