bluuebunny/crossref_metadata_2025 huggingface dataset:
Partial tachyphylaxis to somatostatin (SST) analogues in a patient with acromegaly: the role of SST receptor desensitisation and circulating antibodies to SST analogues
Authors: Wahid ST , Marbach P , Stolz B , Miller M , James RA , Ball SG
Published: January 2005

OBJECTIVE: Somatostatin (SST) analogues are a key option in the management of a variety of conditions, including acromegaly. Tachyphylaxis to SST analogues is not documented in acromegaly. We describe such a phenomenon. DESIGN AND METHODS: A 74-year-old female with acromegaly previously treated with (90)Y implant, external radiotherapy and thrice daily s.c. octreotide had stable GH levels of 19 mU/l. GH progressively rose following switches to lanreotide and depot octreotide as Sandostatin LAR: from 29 to 126 mU/l. Magnetic resonance imaging and (111)In-pentetreotide scanning revealed no tumour growth or alteration in SST receptor (SSTR) status. Tachyphylaxis to SST analogues was considered. Therapy was discontinued and re-introduced in daily 200 microg/24 h increments by continuous s.c. infusion, to a maximum of 1000 microg/24 h, and maintained over 3 weeks with daily, followed by weekly, GH profiles. Competitive (125)I-octreotide radioligand binding assays measured in vitro bio-activity of anti-SST analogue antibodies. In vitro SSTR binding studies utilised SSTR-expressing rat cortex membrane. RESULTS: Median GH fell by 93% from 504 to 39.5 mU/l and rose reproducibly on continued infusion to 120 mU/l. Octreotide withdrawal for 16 h produced a 64% increase in sensitivity. High-affinity IgG anti-lanreotide (IC(50)=187 pmol/l) and anti-octreotide (IC(50)=82 nmol/l) antibody, with no crossreactivity with natural SST, was demonstrated. In vitro inhibition of (125)I-octreotide SSTR binding by anti-SST analogue crossreacting antibody was observed at 1:1 serum dilution. CONCLUSIONS: This is the first report of tachyphylaxis to SST analogues in acromegaly. We believe that the short time course of resensitisation following acute octreotide withdrawal is suggestive of an effect(s) on receptor function or on the receptor signal transduction cascade at sites further downstream, rather than an immune-mediated phenomenon.
Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?
Authors: Rakover Y , Silbergeld A , Lavi I , Masalha R , Shlomo IB
Published: January 2005

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.
Plasma soluble tumor necrosis factor alpha receptors and leptin levels in normal-weight and obese women: effect of adiposity and diabetes
Authors: Bullo M , Garcia-Lorda P , Salas-Salvado J
Published: January 2005

OBJECTIVE: To explore the determinants of the tumor necrosis factor alpha (TNFalpha) system and their relationship with plasma leptin levels. METHODS: We studied a cohort of 157 diabetic and non-diabetic females with a wide range of adiposity distributed into five groups: control--body mass index (BMI) between 19 and 27 kg/m(2) (n=24); obese--BMI between 27 and 40 kg/m(2) (n=63); obese type 2 diabetes mellitus--BMI between 27 and 40 kg/m(2) with diabetes mellitus (n=19); morbid obese--BMI >40 kg/m(2) (n=29); and morbid obese type 2 diabetes mellitus--BMI >40 kg/m(2) with diabetes (n=22). Fasting glucose levels, plasma total triglycerides and cholesterol, high-, low- and very low-density lipoprotein cholesterol were assayed by enzymatic and colorimetric methods. Plasma TNFalpha levels were measured by ELISA assay and insulin and leptin levels by radioimmunoenzymatic assays. Both soluble TNFalpha (sTNFalpha) receptors were measured by immunoenzymometric assays. RESULTS: All groups of patients showed significant increases in both sTNFalpha receptors relative to control. sTNFalpha receptor 1 (sTNFR1) was higher in morbid obese diabetic individuals compared with their non-diabetic counterparts (P=0.003), while sTNFR2 was significantly different between obese and morbid obese subjects (P=0.036). Bivariate correlation analysis showed a significant relationship between both plasma sTNFalpha receptors and BMI, percentage of body fat, fasting glucose, insulin and leptin. In multivariate analysis, both sTNF receptor plasma levels were predicted by percentage of body fat and the presence of diabetes (R(2)=0.20 for sTNFR1 and sTNFR2). When plasma leptin levels were added into the model, this protein and the presence of diabetes explained 27% of the variance of the plasma sTNFR1 levels. CONCLUSION: The presence of diabetes, adiposity or leptin levels are independent determinants of both sTNFalpha receptors. The independent association between plasma TNFalpha receptors and leptin levels in obese patients is consistent with the hypothesis that these proteins could be involved in the same pathway that regulates body adiposity.
Self-adjusted postmenopausal hormone replacement therapy: effects on the biological and immunological profile of FSH and correlation to climacteric symptoms
Authors: Vihtamaki T , Simoni M , Tuimala R , Nieschlag E , Vihko KK
Published: January 2005

OBJECTIVE: The purpose of the present study was to evaluate the hormonal profile of patients of postmenopausal age during estrogen replacement therapy (ERT) with special reference to the serum levels of biologically active FSH (B-FSH) in a self-adjusted ERT model. DESIGN: The hormonal values found have been correlated to climateric symptoms reported by the patients (scored by the Kupperman menopausal index (KI)). METHODS: B-FSH was measured using an assay based on a cell system transfected permanently with FSH receptor cDNA. All women (n=32) applied estradiol percutaneously using 1 mg estradiol-17beta (E(2)) as an initial dose and were encouraged to increase the daily dose until they felt comfortable according to a specific scheme. Twelve of the 32 women were hysterectomized and treated, accordingly, with ERT only; 20 women received megestrol acetate monthly for 10 days. RESULTS: The initial average KI was 30 (range 10-54). A high degree of correlation (r=0.83; P<0.001) was observed between B-FSH and immunologically active FSH (I-FSH). Serum I-FSH and E(2) correlated negatively (r=-0.21; P<0.001); similarly, a negative correlation (r=-0.15; P<0.01) was observed between serum B-FSH and E(2) levels. Serum I-FSH and KI showed modest but significant positive correlation (r=0.13; P<0.01); a somewhat higher degree of correlation (r=0.19; P<0.005) was observed when B-FSH and KI were compared. E(2) showed positive correlation to serum sex-hormone binding globulin levels (r=0.22; P<0.001). CONCLUSIONS: This study shows that the transdermal self-adjusted hormone replacement therapy (HRT) model introduced is suitable for studies on endocrine changes during postmenopausal ERT. The finding of poor correlation between serum E(2) levels and KI emphasizes the importance of hormonal measurements during postmenopausal HRT.
The role of sex steroids in the regulation of insulin sensitivity and serum lipid concentrations during male puberty: a prospective study with a P450-aromatase inhibitor
Authors: Wickman S , Saukkonen T , Dunkel L
Published: January 2005

OBJECTIVE: Our purpose was to study the sex steroid-mediated changes in serum insulin and lipid concentrations in boys during puberty. DESIGN AND METHODS: We treated boys with constitutional delay of puberty either with testosterone plus placebo or with testosterone plus an aromatase inhibitor, letrozole, which inhibits the conversion of androgens to oestrogens. We demonstrated previously that during treatment with testosterone plus letrozole the increase in testosterone concentration was more than 5-fold higher than during treatment with testosterone plus placebo. The concentrations of 17beta-oestradiol, IGF-I and IGF-binding protein-3 increased during testosterone-plus-placebo treatment, but during testosterone-plus-letrozole treatment the concentrations remained unchanged. These divergent changes in the two groups enabled us to study the effects of sex steroids and GH on insulin sensitivity and lipid concentrations. RESULTS: The insulin concentration in the testosterone-plus-placebo-treated group did not change. In contrast, in the testosterone-plus-letrozole-treated group, the concentration decreased during letrozole treatment, indicating improved insulin sensitivity. Changes in insulin and IGF-I concentrations within 12 and 18 months were correlated. In the testosterone-plus-placebo-treated group, the high-density lipoprotein cholesterol concentration did not change but in the testosterone-plus-letrozole-treated group the concentration decreased. The concentrations of low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides did not change in either of the groups. CONCLUSIONS: The findings indicate that androgens do not directly alter insulin sensitivity in boys during puberty. In contrast, the observations suggest tight regulation of glucose--insulin homeostasis by GH in boys at this stage. Furthermore, our findings indicate that sex steroids do not significantly participate in the regulation of serum concentrations of LDL-cholesterol or triglycerides in boys during early and mid-puberty.
Decreased steroidogenic enzyme 17,20-lyase and increased 17-hydroxylase activities in type 2 diabetes mellitus
Authors: Ueshiba H , Shimizu Y , Hiroi N , Yakushiji F , Shimojo M , Tsuboi K , Miyachi Y
Published: January 2005

OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.
Raised serum levels of interleukin-8 and interleukin-18 in relation to bone metabolism in endogenous Cushing's syndrome
Authors: Kristo C , Godang K , Ueland T , Lien E , Aukrust P , Froland SS , Bollerslev J
Published: January 2005

OBJECTIVE: It is well known that patients with endogenous Cushing's syndrome (CS) have decreased bone mass and enhanced risk for osteoporotic fractures, secondary to decreased bone formation and increased bone resorption. Immunological mediators, such as cytokines, have recently been shown to influence bone metabolism, and in the present study we examined serum levels of several cytokines, with known or potential effects on bone homeostasis, in 33 consecutive recruited untreated CS patients and 33 age-, sex- and body mass index-matched healthy controls. METHODS: Cytokine levels were measured by enzyme immunoassay and bone mass by dual-energy X-ray absorptiometry. RESULTS: Our main findings were (i) interleukin (IL)-8 and IL-18 levels were significantly increased in CS patients compared with controls. (ii) Levels of both IL-8 and IL-18 were positively correlated to serum cortisol. (iii) For serum levels of the 'classical' resorptive cytokines, i.e. IL-6 and tumor necrosis factor alpha, no significant differences were found between CS patients and controls. (iv) Raised IL-18 levels were correlated with decreased osteocalcin levels in CS patients. CONCLUSIONS: Our results demonstrated that CS patients have markedly elevated levels of the proinflammatory cytokines IL-8 and IL-18 in spite of high levels of the immunosuppressive hormone cortisol. These cytokines may be involved in the pathogenesis of disturbed bone homeostasis in CS.
Evidence of angiotensin II involvement in prolactin secretion in response to hemorrhage in adrenodemedullated and guanethidine-treated rats
Authors: Machado LJ , Reis AM , Coimbra CC
Published: January 2005

OBJECTIVE: The present experiments were designed to investigate the influence of the renin--angiotensin system (RAS) on prolactin secretion in response to hemorrhage (1.2 ml/100 g body weight (bw)/2 min). METHODS AND RESULTS: Male Wistar rats (250-300 g) were divided into the following experimental groups. (i) Sham-operated animals submitted to intravenous administration of [Sar(1),Thr(8)]-angiotensin II (sarthran), an angiotensin II antagonist (750 ng/100 g bw as a bolus plus an infusion of 25 ng/100 g bw/min over 30 min), which did not alter the prolactin secretion in response to hemorrhage. (ii) Animals submitted to adrenodemedullation which by itself increased the prolactin secretion in response to hemorrhage by 274% (P<0.01). However, sarthran infusion into adrenodemedullated rats completely blocked this increased prolactin secretion in response to hemorrhage (P<0.01). (iii) Intact animals submitted to blockade of sympathetic noradrenergic pathways by pretreatment with guanethidine (10 mg/100 g bw), which also increased the prolactin secretion in response to hemorrhage by 55% (P<0.01). This increased prolactin secretion in response to hemorrhage observed in guanethidine-treated rats was completely blocked by sarthran preinfusion (P<0.01). (iv) Adrenodemedullated animals pretreated with guanethidine, which abolished the prolactin secretion induced by hemorrhage. CONCLUSIONS: Our data suggest a role for circulating catecholamines in the prolactin secretion response to stress. In addition, the experiments reported here demonstrate that RAS has a stimulatory effect on prolactin secretion in circumstances in which sympathetic activity or adrenomedullary secretion is suppressed. These are the first data demonstrating that a physiological prolactin secretion response to stress depends on the RAS.
Craniofacial and brain abnormalities in Laron syndrome (primary growth hormone insensitivity)
Authors: Kornreich L , Horev G , Schwarz M , Karmazyn B , Laron Z
Published: January 2005

OBJECTIVE: To investigate abnormalities in the craniofacial structures and in the brain in patients with Laron syndrome. DESIGN: Eleven patients with classical Laron syndrome, nine untreated adults aged 36-68 years and two children aged 4 and 9 years (the latter treated by IGF-I), were studied. METHODS: Magnetic resonance images of the brain were obtained in all the patients. One patient also underwent computed tomography. The maximal diameter of the maxillary and frontal sinuses was measured and compared with reference values, the size of the sphenoid sinus was evaluated in relation to the sella, and the mastoids were evaluated qualitatively (small or normal). The brain was evaluated for congenital anomalies and parenchymal lesions. RESULTS: In the adult untreated patients, the paranasal sinuses and mastoids were small; in six patients, the bone marrow in the base of the skull was not mature. The diploe of the calvaria was thin. On computed tomography in one adult patient, the sutures were still open. A minimal or mild degree of diffuse brain parenchymal loss was seen in ten patients. One patient demonstrated a lacunar infarct and another periventricular high signals on T2-weighted images. Two patients had cerebellar atrophy. CONCLUSIONS: The present study has demonstrated the important role IGF-I plays in the development of the brain and bony structures of the cranium.
Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy
Authors: Lavery GG , McTernan CL , Bain SC , Chowdhury TA , Hewison M , Stewart PM
Published: January 2005

OBJECTIVE: Mutations in the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension--phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. DESIGN: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. METHODS: We determined allele frequencies for the (CA)n repeat marker within intron I of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. RESULTS: 11 alleles (138-158) for the marker were observed. Allele 152 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P(c)<0.05 where P(c) is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P(c)<0.01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele <152 in DN compared with control subjects (47.3% vs 28.5%, P(c)<0.01), but no difference was observed in LDNN compared with control and DN subjects. CONCLUSIONS: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.
Proinflammatory cytokines inhibit the expression and function of human type I 5'-deiodinase in HepG2 hepatocarcinoma cells
Authors: Jakobs TC , Mentrup B , Schmutzler C , Dreher I , Kohrle J
Published: January 2005

OBJECTIVE: The sick euthyroid syndrome in critically ill patients without primary disease of the thyroid gland is characterised by low serum total triiodothyronine (T3), normal to elevated thyroxine (T4), elevated reverse T3 (rT3) and normal TSH levels. The aim of this work was to clarify if impaired T4 and rT3 5'-deiodination is an underlying mechanism. DESIGN AND METHODS: We analysed the effect of the human recombinant proinflammatory cytokines interleukin (IL)-6 and IL-1beta, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human type I 5'-iodothyronine deiodinase (5'DI) enzyme activity in the human hepatocarcinoma cell line HepG2, i.e. in a homologous human system. Furthermore, we analysed transcriptional effects of the cytokines by transient transfection assays using the luciferase or chloramphenicol acetyltransferase (CAT) reporter genes under the control of 1480 nucleotides of the human 5'DI promoter. RESULTS: IL-6 at 500 pg/ml and TNF-alpha at 25 ng/ml had no significant effect, whereas 100 ng/ml IFN-gamma or 10 ng/ml IL-1beta reduced 5'DI enzyme activity to 77.9 and 59.5% of control values. IFN-gamma did not alter, IL-6 and TNF-alpha moderately decreased (in the case of IL-6 only in the CAT system), and IL-1beta (0.01-10 ng/ml) dose-dependently inhibited 5'DI promoter activity to a minimum of 38.1%. CONCLUSION: IL-1beta inhibited both 5'DI enzyme and promoter activity and, thus, may exert its effect on thyroid hormone metabolism at least partially through direct inhibition of hepatic 5'DI gene transcription.
Binding of heparin to human thyroglobulin (Tg) involves multiple binding sites including a region corresponding to a binding site of rat Tg
Authors: Lisi S , Pinchera A , McCluskey RT , Chiovato L , Marino M
Published: January 2005

OBJECTIVE: Binding of thyroglobulin (Tg) to heparin allows efficient Tg interaction with its endocytic receptor, megalin. Rat Tg (rTg) binds to heparin using an exposed carboxyl terminal region (RELPSRRLKRPLPVK, Arg2489-Lys2503) rich in positively charged residues which is, however, not entirely conserved in human Tg (hTg) (Arg2489-Glu2503, REPPARALKRSLWVE). Here, we investigated whether and how this difference affects binding of heparin. DESIGN: To compare binding of heparin to rTg and hTg. To investigate the role of the sequence 2489-2503 using a peptide-based approach. METHODS: Binding of biotin-labeled heparin to rTg, hTg and to Tg peptides was measured in solid phase assays. RESULTS: Heparin bound to rTg with moderately high affinity (K(d): 34.2 nmol/l, K(i): 37.6 nmol/l) and to hTg with lower affinity (K(d): 118 nmol/l, K(i): 480 nmol/l) and to a lower extent. Binding was dose-dependent and saturable, and was reduced by several specific competitors (Tg itself, unlabeled heparin, lactoferrin). Heparin bound to synthetic peptides corresponding to the rat (rTgP) and to the human (hTgP) Tg sequence 2489-2503. Heparin bound to rTgP to a greater extent and with greater affinity than to hTgP. An antibody against hTgP reduced binding of heparin to intact hTg by 30%, suggesting that in hTg this region is, in part, involved in heparin binding, but also that other regions account for most of the binding. Starting from the sequence of rTgP, we designed 6 synthetic 'mutant' peptides by replacing one amino acid residue of rTgP with the corresponding residue of the sequence of hTgP. Heparin bound to 5 of 6 mutant peptides to a lower extent and with lower affinity than to rTgP. CONCLUSIONS: In spite of a reduced binding ability of the sequence 2489-2503, hTg binds to heparin, in part, using alternative, as yet unidentified, binding sites. Substitution of both positive and neutral residues within the sequence 2489-2503 reduced heparin-binding, suggesting that not only charge, but also sequence and/or conformation, may account for the heparin-binding ability of this region of Tg.
Epidemiological survey on the relationship between different iodine intakes and the prevalence of hyperthyroidism
Authors: Yang F , Teng W , Shan Z , Guan H , Li Y , Jin Y , Hu F , Shi X , Tong Y , Chen W , Yuan B , Wang Z , Cui B , Yang S
Published: January 2005

OBJECTIVE: To investigate the effect of different levels of iodine intake on the prevalence of hyperthyroidism and the impact of universal salt iodization on the incidence of hyperthyroidism. DESIGN: A comparative cross-sectional and longitudinal survey was conducted in three areas with borderline iodine deficiency, mild iodine excess (previously mild iodine deficiency) and severe iodine excess. Universal salt iodization had been introduced 3 years previously except in the area with borderline iodine deficiency. METHODS: In total 16 287 inhabitants from three areas answered a questionnaire concerning the history of thyroid disease. Among them 3761 unselected subjects received further investigations including thyroid function, thyroid autoantibodies, thyroid ultrasonography and urinary iodine excretion. RESULTS: Among areas with median urinary iodine excretion of 103 microg/l, 375 microg/l and 615 microg/l (P<0.05), the prevalence of hyperthyroidism did not differ significantly (1.6%, 2% and 1.2%). The prevalence of subclinical hyperthyroidism was higher in areas with borderline iodine deficiency and mild iodine excess than in the area with severe excess iodine intake (3.7%, 3.9% and 1.1%, P<0.001). The prevalence of Graves' disease and its proportion in hyperthyroidism did not differ among areas. The incidence of hyperthyroidism did not significantly increase after the introduction of universal salt iodization. CONCLUSION: Different iodine intakes under a certain range do not affect the prevalence and type of hyperthyroidism. Subclinical hyperthyroidism is more prevalent in the iodine deficient area than in the severe iodine excessive area. In the area with mild iodine deficiency, the introduction of universal salt iodization may not be accompanied by an increased incidence of hyperthyroidism.
Diurnal rhythm of plasma 1,25-dihydroxyvitamin D and vitamin D-binding protein in postmenopausal women: relationship to plasma parathyroid hormone and calcium and phosphate metabolism
Authors: Rejnmark L , Lauridsen AL , Vestergaard P , Heickendorff L , Andreasen F , Mosekilde L
Published: January 2005

OBJECTIVE: Diurnal variations in plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) have previously only been investigated in young individuals, and these studies have failed to demonstrate a diurnal rhythm. We have studied whether plasma levels of 1,25(OH)(2)D and vitamin D-binding protein (DBP) vary in a diurnal rhythm in postmenopausal women. METHODS: Blood and urine were sampled with 2- and 4-h intervals in order to assess diurnal variations in plasma levels of 1,25(OH)(2)D, DBP and parathyroid hormone (PTH), as well as in plasma levels and urinary excretion rates of calcium and phosphate. Additionally, the free 1,25(OH)(2)D index was calculated (the molar ratio of 1,25(OH)(2)D to DBP). RESULTS: Plasma 1,25(OH)(2)D exhibited a diurnal rhythm (P<0.01) with a nadir in the morning (99+/-12 pmol/l), followed by a rapid increase to a plateau during the day (113+/-13 pmol/l, i.e. 14% above nadir level; P=0.005). A similar pattern of variation was found in plasma levels of DBP with peak levels 15% above nadir levels (P<0.01). The free 1,25(OH)(2)D index did not vary in a diurnal rhythm. PTH and plasma levels and urinary excretions of calcium and phosphate exhibited a diurnal pattern of variation. The diurnal rhythm of DBP was correlated with the rhythm of 1,25(OH)(2)D (r=0.47, P<0.01) and plasma albumin (r=0.76, P<0.01). Moreover, the rhythm of plasma calcium and PTH varied inversely (r=-0.36, P=0.02). CONCLUSIONS: With the disclosure of a diurnal rhythm of total plasma 1,25(OH)(2)D, all major hormones and minerals related to calcium homeostasis have now been shown to exhibit diurnal variations. In clinical studies, the diurnal variations of 1,25(OH)(2)D and DBP must be considered, i.e. blood sampling must be standardised according to the time of day.
Relationship between serum parathyroid hormone, serum calcium and arterial blood pressure in patients with primary hyperparathyroidism: results of a multivariate analysis
Authors: Lumachi F , Ermani M , Luisetto G , Nardi A , Basso SM , Camozzi V , Favia G
Published: January 2005

OBJECTIVE: To evaluate the possible relationship between serum calcium, serum parathyroid hormone (PTH) levels and arterial blood pressure (BP) in patients with primary hyperparathyroidism (HPT). DESIGN: A retrospective population-based study. METHODS: Charts of 194 patients with proven primary HPT were reviewed, and the main clinical and biochemical parameters were recorded. There were 48 men (24.7%) and 146 women (75.3%), with a median age of 59 years (range 23-82 years). Patients who used antihypertensive drugs or hormone replacement therapy had been previously excluded. All patients underwent successful parathyroidectomy, and were cured of their disease. RESULTS: There were no differences (P=NS) between men and women in systolic (143.3+/-19.1 vs 145.4+/-17.1 mmHg) and diastolic (87.1+/-12.3 vs 88.4+/-9.9 mmHg) BP, and in the main biochemical parameters. A significant (P<0.01) correlation was found between (i) serum calcium and serum PTH levels (r=0.39, F=88.36), (ii) age and BP, both systolic (r=0.61, F=118.16) and diastolic (r=0.48, F=64.5), and (iii) body mass index (BMI) and BP (r=0.45 and 0.36 respectively). There was no significant association of serum calcium levels with systolic (r=0.0974, t=1.3422, P=0.18) or diastolic (r=0.1117, t=1.5409, P=0.12) BP, and of serum PTH levels with systolic (r=-0.0349, t=-0.4783, P=0.63) or diastolic (r=-0.0793, t=-1.0913, P=0.28) BP. Multivariate analysis confirmed that none of the independent biochemical parameters significantly correlated with BP, both systolic and diastolic. CONCLUSIONS: In patients with primary HPT there is no relationship between PTH, calcium and BP. Thus, in hyperparathyroid patients, BP should be considered as an independent variable, mainly related to age and BMI.
IGF-I, IGF-I-binding proteins and GH-binding protein in malnourished elderly patients with inflammation receiving refeeding therapy
Authors: Raynaud-Simon A , Perin L , Meaume S , Lesourd B , Moulias R , Postel-Vinay MC , Le Bouc Y
Published: January 2005

OBJECTIVE: To investigate the mechanisms determining the success or failure of refeeding therapy in malnourished elderly patients with inflammation by studying changes in plasma IGF-I, GH-binding protein (GHBP) and IGF-binding protein (IGFBP) levels and IGFBP-3 proteolysis. DESIGN AND METHODS: We studied 15 severely malnourished hospitalized elderly patients. Weight, food intake, plasma albumin, transthyretin, C-reactive protein (CRP), orosomucoid, interleukin-6 (IL-6), IGF-I, intact and proteolytically degraded IGFBP-3 and GHBP levels were determined on admission and during refeeding therapy designed to increase food intake to 40 kcal/kg body weight per day (15% protein). RESULTS: Plasma IGF-I, IGFBP-3 and GHBP levels were significantly low for age on admission in all malnourished elderly patients. They increased in nine patients as nutritional status improved (albuminemia >30 g/l; transthyretinemia >200 mg/l or weight gain >5% of initial body weight) and levels of inflammation markers decreased (group 1). In contrast, plasma IGF-I, IGFBP-3 and GHBP levels remained low in six patients in whom nutritional status failed to improve and levels of inflammation markers increased (group 2). IGF-I showed greater variations than IGFBP-3 or GHBP with respect to nutritional status. High plasma CRP and IL-6 levels were associated with high levels of IGFBP-3 proteolysis. CONCLUSION: Efficient refeeding therapy was associated with a significant increase in IGF-I plasma levels. In patients with severe and persistent inflammation, high levels of proteolysis of IGFBP-3 may have contributed to the low plasma IGF-I levels, persistence of hypercatabolism and lack of improvement in nutritional status.
Homozygous combination of calpain 10 gene haplotypes is associated with type 2 diabetes mellitus in a Polish population
Authors: Malecki MT , Moczulski DK , Klupa T , Wanic K , Cyganek K , Frey J , Sieradzki J
Published: January 2005

OBJECTIVE: The polymorphisms of two genes have recently been associated with complex forms of type 2 diabetes mellitus (T2DM): calpain 10 and peroxisome proliferator-activated receptor-gamma (PPARgamma). Calpain 10 is a member of a large family of intracellular proteases. It was shown in Mexican-Americans and other populations that variants of three single nucleotide polymorphisms (SNPs), -43, -19, and -63, of this ubiquitously expressed protein influence susceptibility to T2DM. However, substantial differences were shown between ethnic groups in at risk alleles and haplotypes as well as in their attributable risk. Thus, it is important to determine the role of calpain 10 in various populations. AIM: To examine the role of calpain 10 SNPs -43, -19, and -63 in genetic susceptibility to T2DM in a Polish population. METHODS: Overall, 377 individuals were examined: 229 T2DM patients and 148 control individuals. The groups were genotyped for calpain 10 SNP-43, SNP-19, and SNP-63. SNP-19 was examined by electrophoresis of the PCR product on agarose gel by size, while the restriction fragment length polymorphism (RFLP) method was used for the two other markers. Differences in allele, genotype, haplotype, and haplotype combination distribution between the groups were examined by chi(2) test. RESULTS: Distributions of alleles, genotypes, and haplotypes at three loci defined by examined SNPs were not significantly different between the groups. However, the homozygote combination of 121 haplotype was more prevalent in the T2DM group than in the controls (17.9% vs 10.1%, P=0.039). No difference was observed in the 112/121 haplotype distribution. This heterozygous haplotype combination was associated with increased risk of T2DM in several populations. CONCLUSION: The results of our study suggest the association of calpain 10 121/121 haplotype combination created by SNPs -43, -19, and -63 with T2DM in a Polish population. However, we were not able to confirm the previously described role of the heterozygous 112/121 haplotype combination in susceptibility to T2DM.
Long-term inhibition of dipeptidyl peptidase IV improves glucose tolerance and preserves islet function in mice
Authors: Reimer MK , Holst JJ , Ahren B
Published: January 2005

OBJECTIVES: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. DESIGN: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 micromol/g body weight) was administered in the drinking water for an 8 week period. RESULTS: DPPIV inhibition reduced plasma DPPIV activity to 0.01+/-0.03 mU/ml vs 3.26+/-0.19 mU/ml in controls (P<0.001). Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet (P=0.029) and in mice fed a high-fat diet (P=0.036). This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P<0.05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16.7+/-2.6 x 10(3) microm(2) in controls to 7.6+/-1.0 x 10(3) microm(2) (P=0.0019). CONCLUSION: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.
Effect of chronic thyroxine treatment on IGF-I, IGF-II and IGF-binding protein expression in mammary gland and liver during pregnancy and early lactation in rats
Authors: Rosato R , Lindenbergh-Kortleve D , Neck J , Drop S , Jahn G
Published: January 2005

OBJECTIVE: Hyperthyroidism in rats produces organ hypertrophy and increases in circulating IGF-I and IGF-binding protein (IGFBP)-3. Chronic treatment with thyroxine (T(4)) during pregnancy advances parturition, blocks lactation and changes several hormone receptors in mammary gland and liver. Since IGFs are implicated in mammary and liver growth and in differentiation, we studied the effects of hyperthyroidism, induced by daily injections of T(4) (0.25 mg/kg). DESIGN AND METHODS: Using quantitative RT-PCR and in situ hybridization, the gene expression of IGF-I, IGF-II and the IGFBPs was determined in mammary gland and liver of rats at estrus and days 7, 14 and 21 of pregnancy (G7, G14, G21), day 1 postpartum (L1) and 3 days after removing the litter (L4). Circulating levels of IGF-I, tri-iodothyronine (T(3)), PRL and GH were measured. RESULTS: T(4) treatment (HT) increased circulating T(3) save on G21, did not change serum IGF-I, increased PRL on G21 and decreased GH on L1. PRL decreased on L1 because of the absence of lactation. Hepatic IGF-I mRNA was low during pregnancy and increased on L4. HT advanced this increase to L1. In controls, liver IGFBP-3 mRNA levels decreased from G14 to G21, whereas IGFBP-4 showed an inverse pattern. HT lowered IGFBP-3 mRNA and increased IGFBP-4. Increases in mammary concentrations of IGF-I, IGFBP-3 and IGFBP-4 mRNAs were seen on G21. HT delayed these peaks to L1. Mammary IGF-II and IGFBP-2 mRNA levels were high on G7 and G14, and fell afterwards, with HT having no effects. IGFBP-5 mRNA decreased during pregnancy and increased on L1. HT increased IGFBP-5 levels in early pregnancy and on L1. IGF-I mRNA localized to connective and epithelial mammary tissue, while IGFBP-2 and IGFBP-5 mRNA was only in epithelial cells. CONCLUSION: These results imply a role for IGF-I, IGFBP-3 and IGFBP-4 in terminal mammary development, while IGF-II and IGFBP-2 may be implicated in early growth. IGFBP-5 has been implicated in mammary apoptosis, and the HT-induced increase may play a role in the premature mammary involution of the HT rats.
A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206 consecutive cases
Authors: Vignali E , Picone A , Materazzi G , Steffe S , Berti P , Cianferotti L , Cetani F , Ambrogini E , Miccoli P , Pinchera A , Marcocci C
Published: January 2005

OBJECTIVE: The traditional surgical approach for patients with primary hyperparathyroidism (PHPT) consists of the identification of at least four glands and in the removal of all hyperfunctioning parathyroid tissue. DESIGN: To evaluate whether intraoperative parathyroid hormone (PTH) monitoring will allow a more limited surgical procedure by confirming complete removal of all hyperfunctioning tissue. METHODS: Plasma samples were obtained from 206 consecutive patients with sporadic PHPT before skin incision, during manipulation of a suspected adenoma, and 5 min (T-5) and 10 min after removal of abnormal parathyroid tissue. PTH was measured by a quick immunochemiluminescent assay (QPTH). The operative success was defined by a decrease of PTH greater than 50% of the highest pre-excision value. RESULTS: A >50% decrease of PTH occurred in 203 patients and was evident at T-5 in the majority of cases. All but three had normal serum calcium the day after surgery and afterwards. PTH concentration did not show a >50% decrease in the remaining three cases after completion of surgery. One patients had negative neck exploration and remained hypercalcemic; the other two had normal serum calcium at follow-up. Thus, the intraoperative QPTH correctly predicted the outcome of surgery in 201 patients (97.5%) (200 true positive and 1 true negative), and provided three false positive and two false negative results. CONCLUSIONS: The intraoperative QPTH measurement represents a useful tool to assist the surgeon during parathyroidectomy. It indicates whether all hyperfunctioning parathyroid tissue has been removed, limiting the procedure to a unilateral neck exploration in most cases.
Controversies in radioiodine therapy: relation to ophthalmopathy, the possible radioprotective effect of antithyroid drugs, and use in large goitres
Authors: Bonnema SJ , Bartalena L , Toft AD , Hegedus L
Published: January 2005

In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction.
Comparison of two different doses of iodide in the prevention of gestational goiter in marginal iodine deficiency: a longitudinal study
Authors: Antonangeli L , Maccherini D , Cavaliere R , Di Giulio C , Reinhardt B , Pinchera A , Aghini-Lombardi F
Published: January 2005

OBJECTIVE: A prospective randomized trial was performed to assess the usefulness of iodine supplementation in the prevention of goiter in pregnant women living in marginally iodine-deficient areas. DESIGN: Eighty-six pregnant women were recruited and randomized in two groups and treated daily for up to six months after delivery with 200 microg iodide (group A) or 50 microg iodide (group B). Sixty-seven women (32 in group A and 35 in group B) completed the study. METHODS: Thyroid volume (TV), thyroid functional parameters and urinary iodine concentration were determined in all subjects at booking, at the 18th-26th, and the 29th-33rd week of gestation, and at the 3rd and 6th month after delivery. RESULTS: A slight but not significant increase in TV during gestation was observed only in group B. After delivery a progressive decrease in TV was documented in both groups, the final TV being significantly reduced with respect to the initial volume in group A. No significant changes in serum free thyroid hormones and TSH concentrations were found during gestation in either group. Postpartum thyroiditis was observed in 5 women (2 in group A, 3 in group B). No side effects were seen. CONCLUSION: The present data indicate that in marginally iodine-deficient areas, the administration of iodide is recommended in pregnancy and lactation. In the conditions of the present trial a dose of 50 microg iodide/day is a safe and effective measure in preventing an increase in TV during pregnancy but a dose of 200 microg iodide/day appeared to be more effective without inducing side effects and without enhancing the frequency of post-partum thyroiditis.
A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults
Authors: Ekman B , Lindstrom T , Nystrom F , Olsson AG , Toss G , Arnqvist HJ
Published: January 2005

OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study. CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.