bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discordant Measures of Androgen-Binding Kinetics in Two Mutant Androgen Receptors Causing Mild or Partial Androgen Insensitivity, Respectively1
Authors: Shkolny Dana L. , Beitel Lenore K. , Ginsberg Jody , Pekeles Gary , Arbour Laura , Pinsky Leonard , Trifiro Mark A. 
Published: January 2014

We have characterized two different mutations of the human androgen receptor (hAR) found in two unrelated subjects with androgen insensitivity syndrome (AIS): in one, the external genitalia were ambiguous (partial, PAIS); in the other, they were male, but small (mild, MAIS). Single base substitutions have been found in both individuals: E772A in the PAIS subject, and R871G in the MAIS patient. In COS-1 cells transfected with the E772A and R871G hARs, the apparent equilibrium dissociation constants (Kd) for mibolerone (MB) and methyltrienolone are normal. Nonetheless, the mutant hAR from the PAIS subject (E772A) has elevated nonequilibrium dissociation rate constants (kdiss) for both androgens. In contrast, the MAIS subject’s hAR (R871G) has kdiss values that are apparently normal for MB and methyltrienolone; in addition, the R871G hAR’s ability to bind MB resists thermal stress better than the hAR from the PAIS subject. The E772A and R871G hARs, therefore, confer the same pattern of discordant androgen-binding parameters in transfected COS-1 cells as observed previously in the subjects’ genital skin fibroblasts. This proves their pathogenicity and correlates with the relative severity of the clinical phenotype. In COS-1 cells transfected with an androgen-responsive reporter gene, trans-activation was 50% of normal in cells containing either mutant hAR. However, mutant hAR-MB binding is unstable during prolonged incubation with MB, whereas normal hAR-MB binding increases. Thus, normal equilibrium dissociation constants alone, as determined by Scatchard analysis, may not be indicative of normal hAR function.
An increased kdiss despite a normal Kd for a given androgen suggests that it not only has increased egress from a mutant ligand-binding pocket, but also increased access to it. This hypothesis has certain implications in terms of the three-dimensional model of the ligand-binding domain of the nuclear receptor superfamily.
Prevalence of Variants in Candidate Genes for Type 2 Diabetes Mellitus in The Netherlands: The Rotterdam Study and the Hoorn Study1
Authors: 't Hart Leen M. , Stolk Ronald P. , Dekker Jacqueline M. , Nijpels Giel , Grobbee Diederick E. , Heine Robert J. , Maassen J. Antonie 
Published: January 2014

We have analyzed the association of variants in the genes for amylin, insulin receptor, insulin receptor substrate-1 (IRS-1), and coagulation factor V with type 2 diabetes mellitus. Random samples of subjects with type 2 diabetes and controls were taken from two population-based studies, the Hoorn and Rotterdam studies, to reduce the risk of artifactual associations.
No association was found for variants in the genes for amylin, IRS-1, and coagulation factor V, nor was there any evidence for epi-static interactions between these gene variants. A significant difference in the frequency of the Arg972 allele of the IRS-1 gene was observed between control subjects from Hoorn and Rotterdam (9.4% vs. 18.6%; P &lt; 0.05). The insulin receptor Met985 variant was found at frequencies of 4.4% and 1.8%, respectively, in type 2 diabetic (n = 433) and normoglycemic patients (n = 799; P &lt; 0.02). Inclusion of data from two other studies yielded a summarized odds ratio of 1.87 (95% confidence interval, 1.06–3.29; P = 0.03).
We conclude that the association between the Met985 variant in the insulin receptor gene and type 2 diabetes, which we previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies. The large regional differences in allele frequency of the Arg972 allele of IRS-1 gene makes genetic association studies of this gene less reliable.
Serum Leptin Response to the Acute and Chronic Administration of Growth Hormone (GH) to Elderly Subjects with GH Deficiency1
Authors: Gill Matthew S. , Toogood Andrew A. , Jones Jenny , Clayton Peter E. , Shalet Stephen M. 
Published: January 2014

In human studies, the principal determinant of serum leptin concentrations is fat mass (FM), but lean mass (LM) also has a significant negative influence. GH treatment in GH deficiency (GHD) alters body composition, increasing LM and decreasing FM, and thus would be expected to alter leptin concentrations. We have therefore examined the acute and chronic effects of GH on serum leptin in 12 elderly GHD subjects (ages 62–85 yr; 3 women and 9 men). FM (kilograms) and LM (kilograms) were determined by dual energy x-ray absortiometry. Leptin, insulin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2, and IGFBP-3 were measured by specific immunoassays. Leptin, insulin, and IGFBP-1 concentrations were log10 transformed, and data were expressed as the geometric mean (−1, +1 tolerance factor). All other data are presented as the mean ± sd.In the acute study, patients received a single bolus dose of GH (0.1 mg/kg BW) at time zero, with blood samples drawn at 0, 12, 24, 48, and 72 h and 1 and 2 weeks. There was a significant rise in leptin, insulin, and IGF-I at a median time of 24 h, followed by a significant fall, and nadir concentrations were reached at a median time of 1.5 weeks (leptin) or 2 weeks (insulin and IGF-I). IGFBP-3 concentrations were also significantly increased, but peak concentrations were not achieved until 48 h. IGF-II, IGFBP-1, and IGFBP-2 exhibited transient decreases before returning to baseline levels. There was no relationship between increased leptin concentrations and either insulin or IGF-I concentrations.In the chronic study, patients received daily GH treatment at doses of 0.17, 0.33, and 0.5 mg/day, each for 3 months (total time on GH, 9 months), and were then followed off GH for a further 3 months. Dual energy x-ray absortiometry was undertaken at 0, 3, 6, 9, and 12 months, and blood samples were drawn at these time points. Over 9 months on GH there was a significant fall in FM and a significant rise in LM, but no change in leptin. There were also significant increments in insulin, IGF-I, and IGFBP-3, whereas IGF-II, IGFBP-1, and IGFBP-2 did not change over 9 months of GH treatment. After 3 months off GH, there was a significant rise in FM and leptin.High dose single bolus GH led to an increase in serum leptin within 24 h apparently independent of changes in insulin or IGF-I. Despite the changes in body composition during chronic GH treatment, there was no change in leptin. However, discontinuation of GH led to a rapid reversal of the favorable body composition and a rise in serum leptin.
Autoantibodies against Aromatic l-Amino Acid Decarboxylase Identifies a Subgroup of Patients with Addison’s Disease1
Authors: Söderbergh Annika , Rorsman Fredrik , Halonen Maria , Ekwall Olov , Björses Petra , Kämpe Olle , Husebye Eystein S. 
Published: January 2014

Autoantibodies against aromatic l-amino acid decarboxylase (AADC) are present in about 50 percent of sera from patients with autoimmune polyendocrine syndrome type I (APS I) but absent in sera from patients with different organ-specific autoimmune diseases, such as insulin-dependent diabetes mellitus, Hashimoto’s thyroiditis, and Graves’ disease. AADC is expressed in the pancreatic β-cells, the liver, and the nervous system; and the presence of AADC antibodies has been shown to correlate to hepatitis and vitiligo in APS I patients.
Among 101 investigated patients with autoimmune Addison’s disease, 15 had high titers of AADC antibodies. According to the clinical characteristics of these patients, only 3 had APS I. The remaining 12 had either isolated Addison’s disease or associated diabetes mellitus, hypothyroidism, vitiligo, alopecia, gonadal failure, and pernicious anemia. Autoantibodies against 21-hydroxylase were present in 9 of 12, whereas autoantibodies against side-chain cleavage enzyme and 17α-hydroxylase were present in 3 of 12. Two patients had only autoantibodies against AADC. DNA was available from 3 of these 12 patients. One of the patients, a woman with Addison’s disease, autoimmune thyroiditis, and premature menopause was heterozygous for a point mutation (G1021A, Val301Met) in the first plant homeodomain zinc finger domain of the autoimmune regulator (AIRE) gene.
The presence of AADC autoantibodies identifies patients with APS I and a subgroup of Addison patients who may have a milder atypical form of APS I or represent a distinct entity. Measurement of autoantibodies against AADC should be included in the evaluation of Addison’s disease.
Is Diagnostic Iodine-131 Scanning Useful after Total Thyroid Ablation for Differentiated Thyroid Cancer?
Authors: Cailleux A. F. , Baudin E. , Travagli J. P. , Ricard M. , Schlumberger M. 
Published: January 2014

A diagnostic iodine-131 (131I) total body scan (TBS) is usually recommended 6 to 12 months after thyroid ablation for differentiated thyroid carcinoma. Its usefulness was evaluated in 256 consecutive patients treated and followed up at the Institut Gustave Roussy for papillary (n = 200), well differentiated (n = 27), or poorly differentiated (n = 29) follicular thyroid carcinomas.
All patients underwent a near-total or total thyroidectomy and 131I ablation with 3.7 GBq (100 mCi). No TBS was performed before 131I ablation. The TBS performed after the administration of 131I to destroy the thyroid remnants showed uptake (&lt;2%) limited to the thyroid bed. A diagnostic 131I-TBS was obtained after withdrawal of T4 treatment, with either 74 MBq (2 mCi; n = 82) or 185 MBq (5 mCi; n = 174), 6 to 12 months after initial treatment, with serum thyroglobulin (Tg) determination. No interference in the Tg assay was found in these 256 patients.
Uptake in the thyroid bed was not detected (total ablation) in 236 patients, was visible but too low to be measured in 19 patients, and attained 1% in only 1 patient. No uptake was found outside the thyroid bed. The serum Tg level, once thyroid hormone treatment had been withdrawn, was below 1 ng/mL in 210 patients, ranged from 1–10 ng/mL in 31 patients, and was above 10 ng/mL in 15 patients. A 131I-TBS performed with 3.7 GBq in nine patients with a Tg level above 10 ng/mL, showed foci of uptake outside the thyroid bed in three patients ; lung metastases were demonstrated by a CT scan in another patient, and palpable lymph node metastases were found in one patient.
In conclusion, a diagnostic 131I-TBS with 74–185 MBq performed 1 yr after thyroid ablation demonstrated no abnormal uptake; it did not correlate with results of Tg determination and only confirmed the completeness of thyroid ablation. The serum Tg level obtained after withdrawal of T4 treatment permits the selection of patients with a Tg level exceeding 10 ng/mL, for scanning with 3.7 GBq (100 mCi).
Administration of a Single Low Dose of Recombinant Human Thyrotropin Significantly Enhances Thyroid Radioiodide Uptake in Nontoxic Nodular Goiter1
Authors: Huysmans Dyde A. , Nieuwlaat Willy-Anne , Erdtsieck Ronald J. , Schellekens Andries P. , Bus Jo W. , Bravenboer Bert , Hermus Ad R. 
Published: January 2014

Radioiodine (131I) is increasingly used as treatment for volume reduction of nontoxic, nodular goiter. A high dose of 131I is often needed because of low thyroid radioiodide uptake (RAIU). We investigated whether pretreatment with a single, low dose of recombinant human TSH (rhTSH; Thyrogen, Genzyme Transgenics Corp.) enhances RAIU in 15 patients with nontoxic, nodular goiter (14 women and 1 man; aged 61 ± 11 yr). Four patients were studied twice, and 1 patient was studied 3 times. RAIU was measured both under basal conditions and after pretreatment (im) with rhTSH, given either 2 h (0.01 mg; n = 7) or 24 h[ 0.01 mg (n = 7) or 0.03 mg (n = 7)] before 131I administration (20–40 μCi). Serum levels of TSH, free T4 (FT4), and total T3 were measured at 2, 5, 8, 24, 48, 72, 96, and 192 h after rhTSH administration.
After administration of 0.01 mg rhTSH, serum TSH rose from 0.7 ± 0.5 to a peak level of 4.4 ± 1.1 mU/L (P &lt; 0.0001), FT4 rose from 16.0 ± 2.6 to 18.5 ± 3.7 pmol/L (P &lt; 0.0001), and T3 rose from 2.10 ± 0.41 to 2.63 ± 0.66 nmol/L (P &lt; 0.0001). After administration of 0.03 mg rhTSH, TSH rose from 0.6± 0.4 to 15.8 ± 2.3 mU/L (P &lt; 0.0001), FT4 rose from 15.2 ± 1.5 to 21.7 ± 2.9 pmol/L (P &lt; 0.0001), and T3 rose from 1.90 ± 0.43 to 3.19 ± 0.61 nmol/L (P &lt; 0.0001). Peak TSH levels were reached at 5–8 h and peak FT4 and T3 levels at 8–96 h after rhTSH administration.
Administration of 0.01 mg rhTSH 2 h before 131I increased 24-h RAIU from 30 ± 11% to 42 ± 10% (P &lt; 0.02), 0.01 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 29 ± 10% to 51 ± 10% (P &lt; 0.0001), and 0.03 mg rhTSH administered 24 h before 131I increased 24-h RAIU from 33 ± 11% to 63 ± 9% (P &lt; 0.0001). After administration of 0.01 mg rhTSH 2 h before 131I, 24-h RAIU did not increase in 1 patient, whereas the increase in 24-h RAIU was less than 10% in 2 other patients. In contrast, administration of rhTSH 24 h before 131I increased 24-h RAIU by more than 10% in all 14 patients (by &gt;20% in 10 and by&gt; 30% in 6).
In conclusion, pretreatment with a single, low dose of rhTSH in patients with nontoxic, nodular goiter increased RAIU considerably. Our observations hold promise that administration of rhTSH before 131I therapy for nontoxic, nodular goiter will allow treatment with lower doses of 131I in these patients.
Expression and Prognostic Value of α-, β-, andγ -Catenins in Differentiated Thyroid Carcinoma
Authors: Böhm Jan , Niskanen Leo , Kiraly Kari , Kellokoski Jari , Eskelinen Matti , Hollmen Sinikka , Alhava Esko , Kosma Veli-Matti 
Published: January 2014

Catenins (α, β, and γ) are a group of intracellular cell adhesion molecules that unite cytoskeleton with extracellular adhesion system. Abnormal expression of these molecules may have prognostic relevance in various carcinomas, including differentiated thyroid carcinoma (DTC). We have, therefore, evaluated the prognostic value of α-, β-, andγ -catenins along with traditional risk factors in 206 consecutive DTC patients by immunohistochemistry.
Papillary carcinomas showed normal staining pattern for α-, β-, andγ -catenins in 124 (60%), 136 (67%), and 94 (46%) cases, respectively. Follicular carcinomas expressed α-, β-, andγ -catenins normally in 16 (48%), 18 (55%), and 8 (32%) cases, respectively. Follicular type of tumor showed more often reduced staining for all catenins than papillary carcinoma (P = 0.009, P = 0.004, and P = 0.002, respectively). Age (&gt;60 yr) and pTNM-stage were related to reduced α- and β-catenin expression levels (P = 0.027 and P = 0.026, respectively) and larger size of the tumor to reduced β- andγ -catenin expressions (P = 0.039 and P = 0.007, respectively). Nodal metastases at the time of primary treatment related to reduced α-catenin expression and distal metastases to reduced β- and γ-catenin staining signals (P = 0.022, P = 0.014, and P = 0.039, respectively). Reduced α-catenin associated with tumor recurrence (P = 0.002) and reduced β-catenin with cancer-related mortality (P = 0.005). The multivariate analysis for recurrence-free survival showed that α-catenin and serum thyroglobulin level 1 yr after primary treatment were prognostic of recurrent disease (hazards ratio, 3.42, P = 0.022; and hazards ratio, 10.03, P = 0.0001). In addition,α -catenin retained its prognostic significance in low-stage patients (P = 0.0151). We propose that the evaluation ofα -catenin expression by immunohistochemistry in DTC patients has prognostic value in addition to that obtained by traditional prognostic factors.
Decrease of Free Thyroxine Levels after Controlled Ovarian Hyperstimulation1
Authors: Muller A. F. , Verhoeff A. , Mantel M. J. , de Jong F. H. , Berghout A. 
Published: January 2014

Controlled ovarian hyperstimulation could lead to opposing effects on thyroid function. Therefore, in a prospective study of 65 women undergoing controlled ovarian hyperstimulation, thyroid hormones, T4-binding globulin, TPO antibodies, gonadotropins, estradiol, and PRL were measured before and after controlled ovarian hyperstimulation.After ovarian stimulation (mean ± se of mean): free T4 decreased, 14.4 ± 0.2 vs. 12.9 ± 0.2 pmol/L (P &lt; 0.0001); thyroid-stimulating hormone increased, 2.3 ± 0.3 vs. 3.0 ± 0.4 mU/L (P &lt; 0.0001); T4-binding globulin increased, 25.2 ± 0.7 vs. 33.9 ± 0.9 mg/L (P &lt; 0.0001); total T4 increased, 98.1 ± 2.3 vs. 114.6 ± 2.5 nmol/L (P &lt; 0.0001); total T3 increased, 2.0 ± 0.04 vs. 2.3 ± 0.07 nmol/L (P &lt; 0.0001); TPO antibodies decreased, 370 ± 233 U/mL vs. 355 ± 224 U/mL (P &lt; 0.0001); LH decreased, 8.1 ± 1.1 vs. 0.4 ± 0.1 U/L (P &lt; 0.0001); FSH did not change, 6.5± 0.6 vs. 7.9 ± 0.9 U/L (P = 0.08); human CG increased, &lt;2 ± 0.0 vs. 195 ± 16 U/L (P &lt; 0.0001); estradiol increased, 359.3 ± 25.9 pmol/L vs. 3491.8 ± 298.3 pmol/L (P &lt; 0.0001); and PRL increased, 0.23 ± 0.02 vs. 0.95 ± 0.06 U/L (P &lt; 0.0001).Because low maternal free T4 and elevated maternal thyroid-stimulating hormone levels during early gestation have been reported to be associated with impaired psychomotor development in the offspring, our findings indicate the need for additional studies in the children of women who where exposed to high levels of estrogens around the time of conception.
Effect of Weight Loss with Reduction of Intra-Abdominal Fat on Lipid Metabolism in Older Men*
Authors: Purnell Jonathan Q. , Kahn Steven E. , Albers John J. , Nevin David N. , Brunzell John D. , Schwartz Robert S. 
Published: January 2014

AbstractHow weight loss improves lipid levels is poorly understood. Cross-sectional studies have suggested that accumulation of fat in intraabdominal stores (IAF) may lead to abnormal lipid levels, increased hepatic lipase (HL) activity, and smaller low density lipoprotein (LDL) particle size. To determine what effect loss of IAF would have on lipid parameters, 21 healthy older men underwent diet-induced weight loss. During a period of weight stability before and after weight loss, subjects underwent studies of body composition, lipids, measurement of postheparin lipoprotein and HL lipase activities, cholesteryl ester transfer protein activity, and insulin sensitivity (Si). After an average weight loss of 10%, reductions in fat mass, IAF, and abdominal sc fat were seen, accompanied by reductions in levels of triglyceride, very low density lipoprotein cholesterol, apolipoprotein B, and HL activity. High density lipoprotein-2 cholesterol and Si increased. In those subjects with pattern B LDL at baseline, LDL particle size increased. Cholesteryl ester transfer protein activity did not change. Changes in IAF and Si correlated with a decrease in HL activity (although not independently of each other). In summary, in men undergoing diet-induced weight loss, only loss of IAF was found to be associated with a reduction in HL, which is associated with beneficial effects on lipid levels.
Age and Gender Predict the Outcome of Treatment for Graves’ Hyperthyroidism*
Authors: Allahabadia Amit , Daykin Jacquie , Holder Roger L. , Sheppard Michael C. , Gough Stephen C. L. , Franklyn Jayne A. 
Published: January 2014

Abstract
The response to treatment in Graves’ hyperthyroidism is unpredictable, and factors postulated to predict outcome have not generally proved clinically useful or been widely adopted in clinical practice. We audited outcome in 536 patients with Graves’ hyperthyroidism presenting consecutively to determine whether simple clinical features predict disease presentation and response to treatment. At presentation males had slightly more severe biochemical hyperthyroidism [free T4: males, 64.3 ± 3.0 pmol/L (mean ± se); females, 61.3 ± 1.7 (P = 0.45); free T3: males, 24.3 ± 1.5 pmol/L; females, 21.0 ± 0.6, (P = 0.04)]. Patients less than 40 yr at diagnosis had more severe hyperthyroidism than patients more than 40 yr old [free T4: &lt;40 yr, 64.3 ± 2.0; &gt;40 yr, 56.7 ± 2.3 (P = 0.02); free T3: &lt;40 yr, 22.8 ± 0.8; &gt;40 yr, 19.0 ± 0.9 (P = 0.003)]. Males had a lower remission rate than females after a course of antithyroid medication [19.6% vs. 40%; odds ratio, 0.37; 95% confidence interval (CI), 0.17–0.79; P &lt; 0.01]. Similarly, patients aged less than 40 yr had a lower remission rate than older patients (32.6% vs. 47.8%; odds ratio, 0.53; 95% CI, 0.32–0.87; P = 0.01). One dose of radioiodine cured hyperthyroidism in fewer males than females (47% vs. 74%; P &lt; 0.0001). Logistic regression analysis demonstrated male sex (odds ratio, 2.80; 95% CI, 1.31–5.98; P = 0.008), serum free T4 concentration at diagnosis (odds ratio, 1.02; 95% CI, 1.0–1.04; P = 0.01), and dose of radioiodine administered (odds ratio, 0.99; 95% CI, 0.99–1.00; P = 0.001) were contributing factors associated with failure to respond to a single dose of radioiodine. As males and younger patients are more likely to fail to respond to medical treatment, and male patients are likewise less likely to respond to a single dose of radioiodine, we suggest that those groups with low remission rates should be offered definitive treatment with radioiodine or surgery soon after presentation and that the value of higher initial doses of radioiodine in males be evaluated
Amino Acid Residue 147 of Human Aldosterone Synthase and 11β-Hydroxylase Plays a Key Role in 11β-Hydroxylation*
Authors: Fisher Angela , Fraser Robert , MC Connell John , Davies Eleanor 
Published: January 2014

AbstractA number of amino acids differ between aldosterone synthase and 11β-hydroxylase. To assess their importance in determining the different functional specificities, we substituted aldosterone synthase-specific (aspartate D147, isoleucine I248, glutamine Q43, and threonine T493) with 11β-hydroxylase-specific amino acids (glutamate E147, threonine T248, arginine R43, and methionine M493), respectively. I248T, Q43R, and T493M had no effect on steroid production compared to wild-type aldosterone synthase. However, CYP11B2-D147E caused a significant increase in corticosterone production and a smaller increase in aldosterone production from 11-deoxycorticosterone (DOC). This appeared to be predominantly due to an increase in the 11β-hydroxylation of DOC to corticosterone mediated by a decrease in Km, which was 1.4 μmol/L for the mutant compared with 5μ mol/L for the wild-type enzyme. CYP11B2-D147E had no effect on the conversion of 11-deoxycortisol to cortisol. The reverse construct (CYP11B1-E147D), substituting the 11β-hydroxylase residue with the aldosterone synthase equivalent, decreased the conversion of DOC to corticosterone, which was mediated by an increase in Km that was 7.5 μmol/L for the mutant compared with 2.5 μmol/L for the wild-type enzyme. Again, the conversion of 11-deoxycortisol to cortisol was unimpaired. Thus, amino acid 147 is involved in the transformation of the 17-deoxysubstrate, but not the 17α-hydroxysubstrate. The results demonstrate that a conservative change in amino acid, even at some linear distance from known active centers, can significantly affect enzyme substrate affinity and subsequent steroid hormone production.