bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Relationship between Glucose Disposal in Response to Physiological Hyperinsulinemia and Basal Glucose and Free Fatty Acid Concentrations in Healthy Volunteers*
Authors: Abbasi Fahim , McLaughlin Tracey , Lamendola Cindy , Reaven Gerald M. 
Published: January 2014

Abstract
This study was initiated to see if defects in the ability of physiological hyperinsulinemia (∼60 μU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (∼10 μU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean ± sem) body mass index of 24.8 ± 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2·min) and insulin (32 mU/m2·min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2·min) and insulin (6 mU/m2·min). The SSPI concentration (mean ± sem) during physiological hyperinsulinemia was 64 ± 3 μU/mL), in contrast to 12 ± 0.4 μU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPGBasal (r = 0.57, P &lt; 0. 01) and FFABasal (r = 0.73, P &lt; 0.001). Furthermore, FFABasal and SSPGBasal were significantly correlated (r = 0.47, P &lt; 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 ± 16 vs. 64 ± 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPGBasal (105 ± 5 vs. 78 ± 7 mg/dL, P &lt; 0.01) and FFABasal (394 ± 91 vs. 104 ± 41, P &lt; 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.
Normal Ovulatory Women with Polycystic Ovaries Have Hyperandrogenic Pituitary-Ovarian Responses To Gonadotropin-Releasing Hormone-Agonist Testing*
Authors: Chang Peter L. , Lindheim Steven R. , Lowre Cheri , Ferin Michel , Gonzalez Frank , Berglund Lars , Carmina Enrico , Sauer Mark V. , Lobo Rogerio A. 
Published: January 2014

Abstract
Women with polycystic ovary syndrome (PCOS) have chronic anovulation and hyperandrogenism and frequently have abnormalities in their lipid profiles and insulin/insulin-like growth factor axis that increase their lifetime risk for cardiovascular disease. Normal ovulatory women may have polycystic ovaries on ultrasonography and yet lack the clinical features of PCOS. To further explore whether ovulatory women without clinical/biochemical hyperandrogenism but with polycystic appearing ovaries (ov-PAO) have subclinical features of PCOS, we prospectively characterized 26 ov-PAO women and matched them by age and body mass index to 25 ovulatory women with normal appearing ovaries (ov-NAO) and to 22 women with PCOS. After an overnight fast, all women had baseline endocrine and metabolic assessments. In addition, a subset of each group of women underwent GnRH-agonist (leuprolide acetate 1 mg sc) testing, ACTH stimulation, and an insulin tolerance test (ITT). At baseline, ov-PAO and ov-NAO women had similar endocrine profiles (LH, LH:FSH, androstenedione, and DHEAS). Compared with ov-NAO, 31% of ov-PAO women had reduced glucose responses after insulin (Kitt), suggesting mild insulin resistance, and 35% had high density lipoprotein levels below 35 mg/dL, a level considered to represent significant cardiovascular risk. After GnRH-agonist, ov-PAO women had response patterns in LH, total testosterone, and 17-hydroxyprogesterone (17-OHP) that were intermediate between ov-NAO and women with PCOS. Ovarian responses were above the normal range in 30–40% of women with ov-PAO. In ov-PAO, peak responses of LH after leuprolide correlated with triglyceride levels (P &lt; 0.05) and peak responses of 17-OHP correlated inversely with Kitt values (P &lt; 0.05). No significant differences were noted with ACTH testing. In conclusion, occult biochemical ovarian hyperandrogenism may be uncovered using GnRH-agonist in ovulatory women with ov-PAO, while adrenal responses remain normal. Subtle metabolic abnormalities may also be prevalent.
Differential Regulation by Troglitazone of Plasminogen Activator Inhibitor Type 1 in Human Hepatic and Vascular Cells1
Authors: Nordt Thomas K. , Peter Karlheinz , Bode Christoph , Sobel Burton E. 
Published: January 2014

Troglitazone, a novel oral insulin sensitizer, normalizes increased plasma activity of plasminogen activator inhibitor type 1 (PAI-1) in hyperinsulinemic patients such as women with polycystic ovary syndrome and patients with type 2 diabetes mellitus. However, underlying mechanisms have not yet been fully elucidated.
Human hepatic and vascular cells, the main sources of circulating PAI-1, were studied in cell culture. In human hepatic cells, PAI-1 accumulated in conditioned medium by 23% within 24 h after exposure to 3 μg/mL troglitazone (P= 0.001). The accumulation depended on the concentration of troglitazone, but not that of insulin (known to stimulate PAI-1 synthesis). By contrast, in human aortic smooth muscle cells, 3μ g/mL troglitazone decreased basal PAI-1 expression by 23% (P = 0.037) and decreased transforming growth factor-β-induced expression by 34% (P = 0.026). Concomitant insulin had no effect. Tissue-type plasminogen activator was decreased by 38% (P = 0.002). In human endothelial cells, PAI-1 was diminished by 32% (P&lt; 0.001), whereas tissue-type plasminogen activator was unaffected.
The results suggest that the reduction in plasma activity of PAI-1 induced by troglitazone in patients may reflect both directly mediated diminution of its elaboration from vessel walls and indirectly mediated reduction of its hepatic synthesis secondary to attenuation of hyperinsulinemia (known to increase the hepatic synthesis of PAI-1).
Serial Analysis of Gene Expression as a Tool to Assess the Human Thyroid Expression Profile and to Identify Novel Thyroidal Genes*
Authors: Pauws E. , Moreno J. C. , Tijssen M. , Baas F. , de Vijlder J. J. M. , Ris-Stalpers C. 
Published: January 2014

AbstractThe assessment of the expression profile of normal human thyroid tissue using serial analysis of gene expression (SAGE) generated a collection of 10,994 sequence transcripts (tags). Each tag represented a messenger RNA transcript, and, in total, 6099 different tags could be distinguished. The presence and abundance of thyroid-specific transcripts showed the overall expression profile to be from a normal thyroid cell. The expression level of several transcripts was confirmed on Northern blot. Seventy percent of tags could not be attributed to a known human gene and, therefore, possibly correspond to novel genes putatively involved in thyroid function. The tag sequence generated by the SAGE technique can be used to further characterize these novel genes. In this way, application of the SAGE technique to thyroid tissue gives insight in the expression profile of a normal thyroid gland and provides the information to characterize novel genes involved in thyroid pathology, such as congenital hypothyroidism and thyroid neoplasia.
Glucocorticoid Stimulation of Corticotropin-Releasing Hormone Gene Expression Requires a Cyclic Adenosine 3′,5′-Monophosphate Regulatory Element in Human Primary Placental Cytotrophoblast Cells*
Authors: Cheng You-Hong , Nicholson Richard C. , King Bruce , Chan Eng-Cheng , Fitter John T. , Smith Roger 
Published: January 2014

AbstractProduction of placental CRH, which is identical to the peptide synthesized and secreted in the hypothalamus, has been linked to human parturition. Glucocorticoids stimulate placental CRH secretion and messenger ribonucleic acid expression, in contrast to their inhibition of CRH synthesis in the hypothalamus. A positive feedforward loop involving glucocorticoid-CRH-ACTH-glucocorticoid is thought to drive the exponential increase in placental CRH leading to delivery. Tissue-specific effects of glucocorticoids on CRH expression are therefore of interest. Using human primary placental cells, we investigated the mechanism by which glucocorticoids stimulate placental CRH gene expression. Nuclear run-on transcription shows that in human placental cells glucocorticoids up-regulate transcription of human CRH (hCRH). Using transient transfection assays we demonstrate that dexamethasone up-regulates both basal and cAMP-stimulated hCRH promoter activity, correlating well with the increase in endogenous CRH peptide levels. Through mutagenesis and deletion analyses we show that dexamethasone stimulation of hCRH gene transcription requires a functional cAMP regulatory element (CRE); this CRE is adequate to confer dexamethasone stimulation upon a heterologous promoter, and electrophoretic mobility shift assay studies show that a placental nuclear protein specifically binds to the hCRH CRE.
Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in Vitro*
Authors: Pentikäinen Virve , Erkkilä Krista , Suomalainen Laura , Parvinen Martti , Dunkel Leo 
Published: January 2014

AbstractThe necessity of estrogens for male fertility was recently discovered in studies on both estrogen receptor α knockout and aromatase (cyp 19 gene) knockout mice. However, direct testicular effects of estrogens in male reproduction have remained unclear. Here we studied the protein expression of ERα and the recently described estrogen receptor β in the human seminiferous epithelium and evaluated the role of 17β-estradiol, the main physiological estrogen, in male germ cell survival. Interestingly, both estrogen receptors α and β were found in early meiotic spermatocytes and elongating spermatids of the human testis. Furthermore, low concentrations of 17β-estradiol (10−9 and 10−10 mol/L) effectively inhibited male germ cell apoptosis, which was induced in vitro by incubating segments of human seminiferous tubules without survival factors (i.e. serum and hormones). Dihydrotestosterone, which, in addition to estradiol, is an end metabolite of testosterone, was also capable of inhibiting testicular apoptosis, but at a far higher concentration (10−7 mol/L) than estradiol. Thus, estradiol appears to be a potent germ cell survival factor in the human testis. The novel findings of the present study together with the previously reported indirect effects of estrogens on male germ cells indicate the importance of estrogens for the normal function of the testis.
Long-Term Follow-Up Results of Postoperative Radiotherapy in 36 Patients with Acromegaly
Authors: Biermasz Nienke R. , van Dulken Hans , Roelfsema Ferdinand 
Published: January 2014

In acromegaly, pituitary irradiation is a slow, but effective, intervention in decreasing GH concentration. Few studies addressing the outcome of radiotherapy have used the currently accepted strict criteria for remission in the analysis of data. These studies report a low percentage of remission after radiotherapy. Doubt has especially been raised as to whether radiotherapy is effective in normalizing serum insulin-like growth factor (IGF)-I concentration. We analyzed the long-term follow-up data of postoperatively administered radiotherapy in 36 patients with postoperative persistent acromegaly, using both the normalization of GH suppression during oral glucose loading (GTT) and the normalization of IGF-I concentration as criteria for remission. Before radiotherapy, mean suppressed GH was 9.8 ± 1.9 mU/L (n = 31), and mean IGF-I concentration was 44.3 ± 3.9 nmol/L, equivalent to + 4.76 ± 0.78 age-related IGF-I sd score (n = 13). The median radiation dose was 40 Gray (range, 25–50 Gray).
At 5, 10, and 15 yr follow-up, 18 out of 30 patients (60%), 23 out of 31 patients (74%), and 16 out of 19 patients (84%), respectively, achieved normal serum IGF-I concentration. At the last assessment of all patients, after a mean follow-up period of 139 ± 12 months, 27 out of 36 (75%) patients had a normal IGF-I concentration without additional medication, whereas 5 patients still required treatment with octreotide. Remission, as judged by normalization of GH suppression during GTT, was documented in 65% of patients from 2–5 yr after radiotherapy (n = 34); in 69% of patients, up to 10 yr after radiotherapy (n = 29); and in 71% of patients, up to 15 yr post irradiation (n = 17). At the latest assessment, a mean of 125± 11 months after radiotherapy, 71% of patients (n = 35) were in remission, as defined by normal suppression of serum GH during GTT. Remission, as judged by normalization of both GTT and IGF-I, was found in 40% of patients 3–5 yr after radiotherapy (n = 30); in 61% of patients, 6–10 yr after radiotherapy (n = 28); in 65%, after 11–15 yr after radiotherapy (n = 17); and in 63% of patients, at the end of the follow-up period (n = 35). Substitution of one or more pituitary hormone deficiencies was required in 11% of patients postoperatively; in 29%, 5 yr after radiotherapy; in 54%, 10 yr after radiotherapy; and in 58%, more than 15 yr after radiotherapy. Our findings support the use of radiotherapy as an effective intervention in the treatment of residual clinical activity of disease after surgery for acromegaly.
Genome Screen for QTLs Contributing to Normal Variation in Bone Mineral Density and Osteoporosis*
Authors: Koller D. L. , Econs M. J. , Morin P. A. , Christian J. C. , Hui S. L. , Parry P. , Curran M. E. , Rodriguez L. A. , Conneally P. M. , Joslyn G. , Peacock M. , Johnston C. C. , Foroud T. 
Published: January 2014

Abstract
A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans).
The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.
Genome-Wide Scan of Obesity in Finnish Sibpairs Reveals Linkage to Chromosome Xq24*
Authors: Öhman Miina , Oksanen Laura , Kaprio Jaakko , Koskenvuo Markku , Mustajoki Pertti , Rissanen Aila , Salmi Jorma , Kontula Kimmo , Peltonen Leena 
Published: January 2014

Abstract
Obesity is a multifactorial trait with evidence of a genetic component. Obesity is very common in all westernized countries, including Finland, where 10% of the adult population has a body mass index of 32 kg/m2 or more. Here we report results from a three-stage genome-wide scan of obesity in 188 affected subjects (body mass index,≥ 32 kg/m2) from 87 Finnish families. Initially, 374 markers with an average density of 10 centimorgans were genotyped. The strongest evidence for linkage to obesity was detected on chromosome Xq24, with the marker DXS6804 providing a maximum likelihood score (MLS) 3.14 in a model-free 2-point sibpair analysis. Fine-mapping in an extended sample set of 367 affected subjects from 166 families yielded a multipoint MLS of 3.48 over this X-chromosomal region. The Xq24 region contains a plausible candidate gene, serotonin 2C receptor, variants of which have been shown to predispose to obesity and type II diabetes in mice. Another chromosomal region also provided suggestive evidence of linkage, an area on 18q21, flanking the melanocortin-4 receptor, where a 2-point MLS of 2.42 with marker D18S1155 was obtained with a set of 367 affected subjects. In conclusion, our results in this Finnish study sample suggest that a locus on chromosome Xq24 influences the risk of obesity.
Circulating Thyroglobulin Transcytosed by Thyroid Cells Is Complexed with Secretory Components of Its Endocytic Receptor Megalin*
Authors: Marinò Michele , Chiovato Luca , Mitsiades Nicholas , Latrofa Francesco , Andrews David , Tseleni-Balafouta Sophia , Collins A. Bernard , Pinchera Aldo , McCluskey Robert T. 
Published: January 2014

AbstractAfter its endocytosis from the colloid, some thyroglobulin (Tg) is transcytosed intact across thyrocytes, accounting in part for its presence in the circulation. We previously showed that megalin (gp330), an endocytic Tg receptor, mediates apical to basolateral Tg transcytosis. Here we investigated whether a portion of megalin remains combined with Tg after its transcytosis, using studies with cultured thyroid cells and in vivo observations.FRTL-5 cells, a rat thyroid cell line, cultured on filters in dual chambers form tight junctions and exhibit features of polarity, with expression of megalin exclusively on the upper (apical) surface. After the addition of unlabeled Tg to the upper chamber and incubation at 37 C, some Tg was transcytosed intact across FRTL-5 cells into the lower chamber. Two antimegalin ectodomain antibodies precipitated transcytosed Tg in fluids collected from the lower chamber. After the addition of Tg to surface-biotinylated FRTL-5 cells, an anti-Tg antibody and the two antimegalin ectodomain antibodies precipitated high molecular mass biotinylated material in fluids collected from the lower chamber, corresponding to much of the megalin ectodomain, as well as smaller amounts of lower molecular mass material. The results indicate that Tg transcytosed across FRTL-5 cells remains complexed with megalin ectodomain components, which we refer to as megalin secretory components.In aminotriazole-treated rats, which develop increased megalin-mediated Tg transcytosis, antimegalin antibodies precipitated some of the Tg in the serum. Tg was also precipitated by antimegalin antibodies in sera from patients with Graves’ disease, in which we found increased megalin expression on the apical surface of thyrocytes. In contrast, in thyroidectomized patients with metastatic papillary thyroid carcinoma, in whom Tg is directly secreted by neoplastic thyroid cells into the circulation rather than transcytosed, serum Tg was not precipitated by antimegalin antibodies. The detection of Tg-megalin complexes may help identify the source of serum Tg in patients with thyroid diseases.
Phenotypic Diversity and Testosterone-Induced Normalization of Mutant L712F Androgen Receptor Function in a Kindred with Androgen Insensitivity*
Authors: Holterhus Paul-Martin , Sinnecker Gernot H. G. , Hiort Olaf 
Published: January 2014

Abstract
Molecular causes of phenotypic diversity in androgen insensitivity syndrome, occurring even in the same family, have rarely been identified. We report on a family with four affected individuals, three brothers (B1–3) and their uncle, displaying strikingly different external genitalia: B1, ambiguous; B2, severe micropenis; B3, slight micropenis; and uncle, micropenis and penoscrotal hypospadias. All had been assigned a male gender. We detected the same L712F mutation of the androgen receptor (AR) gene in each subject. Methyltrienolone binding on cultured genital skin fibroblasts of B2 suggested moderate impairment of the ligand-binding domain [maximal binding capacity, 38.2 fmol/mg protein (normal); Kd, 0.21 nmol/L; normal range, 0.03–0.13 nmol/L]. In trans-activation assays, the mutant 712F-AR showed considerable deficiency at low concentrations of testosterone (0.01–0.1 nmol/L) or dihydrotestosterone (0.01 nmol/L). Remarkably, this could be fully neutralized by testosterone concentrations greater than 1.0 nmol/L. Hence, the 712F-AR could switch its function from subnormal to normal within the physiological concentration range of testosterone. This was reflected by an excellent response to testosterone therapy in B1, B2, and the uncle. Taking into account the well documented individual and time-dependent variation in testosterone concentration in early fetal development, our observations clearly illustrate the potential impact of varying ligand concentrations for distinct cases of phenotypic variability in androgen insensitivity syndrome.
Differential Expression of Estrogen Receptor α and β Immunoreactivity in the Human Supraoptic Nucleus in Relation to Sex and Aging*
Authors: Ishunina Tatjana A. , Kruijver Frank P. M. , Balesar Rawien , Swaab Dick F. 
Published: January 2014

AbstractThe dorsolateral supraoptic nucleus (dl-SON) is the main production site of plasma arginine vasopressin (AVP). Plasma AVP levels and the activity of AVP neurons in humans are higher in males than in premenopausal females. On the other hand, an increased activity of AVP neurons becomes prominent in postmenopausal women who have strongly decreased estrogen levels. As estrogens are presumed to inhibit AVP production in a receptor-mediated way, we studied estrogen receptor (ER) α and β immunoreactivity in the dl-SON. Hypothalami of 34 controls were subdivided into 4 groups within a 50-yr boundary (young men, young women, elderly men, and elderly women). The AVP part of the dl-SON of young women contained 50 times more neurons with ERβ nuclear staining than that in young men and 250 times more than that in elderly women. In addition, young women also showed more ERβ cytoplasmic staining than young men and elderly women. In contrast to the ERβ immunoreactivity, no differences were found in the number of ERα-positive neurons in the 4 groups, but the age and sex pattern of ERα staining was basically opposite that of ERβ. Significant correlations between the percentage of ERβ- and ERα-positive and -negative AVP neurons and age were found in women, but not in men. Our data demonstrate for the first time a strong decrease of ERβ and an increase of ERα immunoreactivity in AVP neurons of the dl-SON of postmenopausal women. Both receptor changes are proposed to participate in the activation of the AVP neurons in postmenopausal women.