bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent Genetic Factors Determine the Amount and Distribution of Fat in Women after the Menopause1
Authors: Samaras K. , Spector T. D. , Nguyen T. V. , Baan K. , Campbell L. V. , Kelly P. J. 
Published: January 2014

Abstract
Central adiposity is a strong predictor of cardiovascular disease in women. We studied postmenopausal twins to explore the strength and the relationship between genetic influences on body fat and its distribution in a group where cardiovascular disease is the major cause of mortality. Healthy twin women were recruited from a national media campaign. One hundred nineteen monozygotic (MZ) and 97 dizygotic twin pairs were studied (mean ± se age 60 ± 0.3 yr, 10 ± 0.4 yr post menopausal). Total and central body fat were measured by dual-energy x-ray absorptiometry. Intrapair resemblance was significantly greater in MZ pairs for total fat (MZ vs. dizygotic, r = 0.70 ± 0.05 vs. r = 0.46 ± 0.08, P = 0.005) and central fat (r = 0.62 ± 0.06 vs. r = 0.35 ± 0.09, P = 0.005), suggesting a strong genetic influence on these traits. Model-fitting analysis indicated that genetic factors contribute up to 60% of total population variance in both total and central body fat. The heritability of central fat remained, after adjustment for the heritability of total fat, suggesting an independent genetic influence on fat distribution. These results were unchanged after adjusting for the effects of estrogen replacement and smoking.
In conclusion, total adiposity and central abdominal fat mass in normal postmenopausal women are under strong genetic influence. The data suggest that some of the genes responsible for central adiposity and its metabolic sequelae will be different from those responsible for total adiposity.
Fluoride at Mitogenic Doses Induces a Sustained Activation of p44mapk, but Not p42mapk, in Human TE85 Osteosarcoma Cells*
Authors: Wu Li-Wha , Yoon Hyun Koo , Baylink David J. , Graves Lee M. , Lau K.-H. William 
Published: January 2014

AbstractFluoride, at micromolar concentrations, stimulates bone cell proliferation in vitro. In this study, we sought to test whether fluoride at mitogenic doses increases the tyrosyl phosphorylation level and specific activity of a mitogen-activated protein kinase (MAPK) in human TE85 osteosarcoma cells. Analysis by immunoprecipitation with antiphosphotyrosine antibody followed by Western analysis using an anti-pan extracellular signal-regulated kinase antibody revealed that fluoride at the optimal mitogenic dose (i.e. 100 μmol/L) induced a time-dependent increase in the steady state tyrosyl phosphorylation level of p44mapk, but not p42mapk, with the maximal increase (4- to 13-fold) after 1–3 h fluoride treatment. The effect was sustained in that a 9-fold increase was seen after 12 h of the fluoride treatment. The sustained nature of the effect is consistent with an inhibition of dephosphorylation rather than a direct stimulation of phosphorylation. The fluoride effect on the tyrosyl phosphorylation level of p44mapk was dose dependent, with the optimal dose being 100μ mol/L fluoride. The mitogenic dose of fluoride also increased the specific activity and the in-gel kinase activity of p44mapk, but not that of p42mapk, in a time-dependent manner similar to the effect on the p44mapk tyrosyl phosphorylation level. Fluoride at the same micromolar doses did not increase cell proliferation, tyrosyl phosphorylation, or specific activity of any MAPK in human skin foreskin fibroblasts, which are fluoride-nonresponsive cells. Consistent with the interpretation that the effect of fluoride on the steady state tyrosyl phosphorylation level of p44mapk is a consequence of an inhibition of a phosphotyrosyl phosphatase (PTP), mitogenic doses of orthovanadate, a bone cell mitogen and a PTP inhibitor, also increased the steady state tyrosyl phosphorylation level of p44mapk, but not p42mapk, in a time-dependent sustained manner similar to that observed with fluoride. Together, these findings support the concept that inhibition of a PTP activity in bone cells could lead to an activation of MAPK activity.
Spontaneous Feminization in a 46,XX Female Patient with Congenital Lipoid Adrenal Hyperplasia Due to a Homozygous Frameshift Mutation in the Steroidogenic Acute Regulatory Protein*
Authors: Bose Himangshu S. , Pescovitz Ora Hirsch , Miller Walter L. 
Published: January 2014

AbstractThe most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in the cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete absence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) protein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of StAR-independent steroidogenesis to persist until the accumulation of intracellular lipid deposits destroys steroidogenic capacity. This model would predict that the steroidogenic cells of the ovaries of affected 46,XX females should remain undamaged until puberty, at which time low levels of StAR-independent estrogen biosynthesis should be detectable. We describe a 15.5-yr-old 46,XX female with a classic history of lipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift mutation 261delT. This is the first adolescent female with lipoid CAH who has undergone spontaneous feminization and who has been analyzed genetically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subsequent damage from accumulation of cholesterol esters.
Elevated Serum Insulin-Like Growth Factor-Binding Protein 2 (IGFBP-2) and Decreased IGFBP-3 in Epithelial Ovarian Cancer: Correlation with Cancer Antigen 125 and Tumor-Associated Trypsin Inhibitor1
Authors: Flyvbjerg Allan , Mogensen Ole , Mogensen Bent , Nielsen Ole Steen 
Published: January 2014

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) recently have been shown to play a physiological role in the female genital system, including the ovarian follicular system. However, little is known about the role of the IGF system in malignant ovarian disease. To assess possible mutual correlations between alterations in circulating IGFBP profiles and tumuor markers in patients with epithelial ovarian cancer, we performed an RIA for IGFBP-2 and IGFBP-3 and a Western ligand blotting (WLB) in serum samples from 20 patients with epithelial ovarian cancer, 10 patients with benign ovarian tumors, and 8 healthy age-matched controls. The epithelial ovarian cancer group had a mean IGFBP-2 level that was 253% (RIA) and 105% (WLB) above that of controls. IGFBP-2 even correlated positively with the highly sensitive serum tumor marker, cancer antigen 125 (CA 125) (r = 0.71, P &lt; 0.001) but not with the less sensitive tumor-associated trypsin inhibitor. In contrast, serum IGFBP-3 (by RIA and WLB) was decreased in patients with ovarian cancer, and IGFBP-3 proteolytic activity was detectable in some of the patients. Neither IGFBP-3 nor IGFBP-3 proteolytic activity correlated with CA 125; but the former correlated inversely, and the latter positively, with tumor-associated trypsin inhibitor.In conclusion, IGFBP-2 levels are high in serum of epithelial ovarian cancer patients, and the increment in serum IGFBP-2 correlates positively with CA 125. Alterations in serum IGFBP-2 levels may, therefore, serve as a potential additional marker for ovarian cancer.
Metabolism of Oral Glucose in Pancreas Transplant Recipients with Normal and Impaired Glucose Tolerance1
Authors: Christiansen E. , Tibell A. , Vølund Aa. , Holst J. J. , Rasmussen K. , Schäffer L. , Madsbad S. 
Published: January 2014

To gain insight into the pathophysiology of impaired glucose tolerance in pancreas transplantation, glucose kinetics and insulin secretion were assessed after an oral glucose load in four combined pancreas-kidney recipients with impaired glucose tolerance (IPx), in five combined pancreas-kidney recipients with normal glucose tolerance, in six nondiabetic kidney transplant recipients, and in eight normal subjects employing a dual isotope technique. β-Cell function was evaluated by calculating prehepatic insulin secretion rates, which subsequently were correlated to the ambient glucose concentrations to obtain an index of β-cell responsiveness. Oxidative and nonoxidative glucose metabolism were assessed by indirect calorimetry. Basal insulin secretion rates, the glucose-stimulated early insulin secretion rates, as well as β-cell responsiveness were markedly reduced in IPx than in the glucose-tolerant transplant subjects. Total systemic glucose appearance was similar in the groups with apparently comparable inhibition of systemic glucose release and increase in exogenous glucose appearance. The hyperglycemic response in IPx was due to a significant reduction in the glucose disappearance rates during the first 2 h after glucose ingestion. Nonoxidative glucose metabolism increased significantly less in IPx than in glucose-tolerant groups. Glucagon secretion was less suppressed in the early part of the study in IPx, which may have contributed to the excessive hyperglycemia.
In conclusion, IPx after pancreas transplantation was characterized by 1) impaired early insulin secretion, 2) reduced β-cell responsiveness, 3) reduced glucose uptake, 4) impaired nonoxidative glucose metabolism, and 5) impaired early inhibition of glucagon secretion.
Free Insulin-Like Growth Factor I Serum Levels in 1430 Healthy Children and Adults, and Its Diagnostic Value in Patients Suspected of Growth Hormone Deficiency1
Authors: Juul Anders , Holm Kirsten , Kastrup Knud W. , Pedersen Søren A. , Michaelsen Kim Fleischer , Scheike Thomas , Rasmussen Susanne , Müller Jørn , Skakkebæk Niels E. 
Published: January 2014

Serum levels of total insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) reflect endogenous GH secretion in healthy children, which makes them good diagnostic markers for screening of GH deficiency (GHD) in short children, although some controversy still exists. Only a minor fraction of the total IGF-I circulates in its free form, which is believed to be the biologically active form. However, our knowledge of the clinical or physiological value of determination of free IGF-I in serum is limited at present. In adults, the diagnostic value of total IGF-I and IGFBP-3 determinations in patients suspected of GHD has only been reported in a few studies, whereas no previous reports on the diagnostic value of free IGF-I levels in adults suspected of GHD exist.
Serum levels of free IGF-I were determined in 1430 healthy children, adolescents, and adults by a newly developed, commercially available immunoradiometric assay (Diagnostic Systems Laboratories) to establish valid normative data for this analysis. We studied the diagnostic value of free IGF-I in relation to total IGF-I and IGFBP-3 determinations in adults who were suspected of GHD. A GH provocative test, using oral clonidine, was performed in 108 adult patients who had previously been treated with GH in childhood.
In healthy subjects, free IGF-I levels increased during childhood, with the highest mean values during puberty. After puberty, a subsequent decline in serum levels of free IGF-I was apparent. We found unmeasurable free IGF-I values in 34 of the prepubertal children (3.3%). All individuals over 8 yr of age had measurable free IGF-I levels that amounted to approximately 1% of the total IGF-I concentrations. Free IGF-I levels were below −2 sd in 56 of 79 GHD patients (sensitivity, 71%) and above −2 sd in 24 of 29 patients with a normal GH response (specificity, 83%). Multiple linear regression analysis demonstrated that free IGF-I was significantly dependent on peak GH levels, duration of the disease, and number of other pituitary axes affected.
We conclude that free IGF-I serum levels increase during childhood with a peak in puberty, whereafter free IGF-I levels return to prepubertal levels. Three percent of healthy prepubertal children had unmeasurable free IGF-I levels using this assay. We found that determination of the free IGF-I serum concentration may predict the outcome of a GH provocative test in adults suspected of GHD, but that a single determination of free IGF-I offered no significant advantage compared to determination of total IGF-I or IGFBP-3 serum levels.
Short-Term Variations in Bone Remodeling Biochemical Markers: Cyclical Etidronate and Alendronate Effects Compared
Authors: Bettica P. , Bevilacqua M. , Vago T. , Masino M. , Cucinotta E. , Norbiato G. 
Published: January 2014

Abstract
Bone-remodeling markers have been proposed to monitor antiosteoporotic therapy, as substantial changes in these markers usually occur in a relatively short time interval. In this study we have evaluated the short term effects of two bisphosphonates on bone-remodeling markers with the aim of 1) defining the shortest reliable time interval after which markers should be measured, and 2) comparing the effects of different bisphophonates. To do so, 74 postmenopausal women with a lumbar spine t score of at least −1 were randomly allocated to 4 different treatments: calcium carbonate (500 mg/day; n = 18), 5 mg/day alendronate (A5; n = 18), 10 mg/day alendronate (A10; n = 20), and cyclical etidronate (CE; n = 18). Serum and 24-h urine samples were collected at baseline and 14, 28, 56, and 84 days after the beginning of therapy. Type I collagen N-terminal (NTx) and C-terminal (CTx) telopeptides and total deoxypyridinoline (tDPD) were measured in urine and normalized for urinary creatinine excretion. Osteocalcin and bone alkaline phosphatase in serum were measured. Alendronate (at both doses) and CE significantly decreased bone-remodeling markers, whereas calcium carbonate did not. Bone resorption markers reduction reached a plateau 14 (A10) or 28 (A5 and CE) days after the beginning of treatment, whereas osteocalcin and bone alkaline phosphatase were significantly reduced at 56 (A10) and 84 (CE) days. The global effects of alendronate and CE on NTx and CTx (calculated as the area under the curve) were significantly different from those of calcium (P &lt; 0.05), but were not significantly different from each other. The percent change from baseline obtained with tDPD, NTx, or CTx during bisphosphonate treatment were significantly different (P &lt; 0.05), but this difference disappeared when the variability in the calcium carbonate group was taken into account. In conclusion, this study shows that 1) etidronate and alendronate induce a significant and rapid reduction in bone-remodeling markers; 2) the changes in NTx, CTx, and tDPD urinary excretions reach a plateau after 2–4 wk of treatment; and 3) short term treatments with CE or alendronate induce similar changes in the urinary excretion of NTx and CTx.
A Change from Stimulatory to Blocking Antibody Activity in Graves’ Disease during Pregnancy1
Authors: Kung A. W. C. , Jones B. M. 
Published: January 2014

Remission of Graves’ disease (GD) during pregnancy with recrudescence after delivery is commonly observed. However, as pregnancy is associated with type 2 rather than type 1 cytokine production, a decrease in thyroid-stimulating antibody (TSAb) activity alone is unlikely to account for the remission during pregnancy. We hypothesized that a change in the antibody characteristics may occur as pregnancy advances. Fifteen women were studied in the first, second, and third trimesters of pregnancy and 4 months postpartum. TSH receptor antibodies were determined using human thyroid cell cultures, and lymphocyte subsets were measured by flow cytometry.Median TSAb (determined by cAMP release) decreased from 280% (96–3200) to 130% (range, 35–350; P &lt; 0.05) during pregnancy, but no significant change was noted with the TSH binding inhibitory antibody (TBII; determined by RRA). Thyroid stimulation-blocking antibody (TSBAb; inhibition of TSH-stimulated cAMP release) increased from 16 ± 9% to 43 ± 16% (mean ± sd; P &lt; 0.005). The increase in TSBAb was observed even among those patients who were in clinical remission before pregnancy. Overall, a negative correlation was observed between TSBAb activities and free T4 levels during pregnancy (r = −0.279; P &lt; 0.05). Reciprocal changes in TSAb, TBII, and TSBAb levels were observed in the seven patients who relapsed during the postpartum period. In comparison, the healthy pregnant women (n = 14) were all negative for TSAb, TBII, and TSBAb throughout pregnancy.The absolute number of T lymphocytes, T helper cells, and natural killer cells, but not B cells, decreased significantly during pregnancy in both healthy women and GD patients. GD patients had significantly more CD5+ B cells at all stages of pregnancy compared to controls. In conclusion, a change in specificity from stimulatory to blocking antibodies was observed in GD patients during pregnancy and may contribute to the remission of GD during pregnancy.
Polymerase Chain Reaction-Based Microsatellite Polymorphism Analysis of Follicular and Hürthle Cell Neoplasms of the Thyroid1
Authors: Segev Dorry L. , Saji Motoyasu , Phillips Grace S. , Westra William H. , Takiyama Yumi , Piantadosi Steven , Smallridge Robert C. , Nishiyama Ronald H. , Udelsman Robert , Zeiger Martha A. 
Published: January 2014

Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P &lt; 0.001) and 2p (P &lt; 0.05) by Fisher’s exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P &lt; 0.0005, by McNemar’s test).In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.
Study of a Kindred with Classic Congenital Adrenal Hyperplasia: Diagnostic Challenge due to Phenotypic Variance1
Authors: Chin Daisy , Speiser Phyllis W. , Imperato-McGinley Julianne , Dixit Naznin , Uli Naveen , David Raphael , Oberfield Sharon E. 
Published: January 2014

We sought to determine the concordance of the phenotype and genotype in a kindred with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variation in phenotypic expression within this family underscores the difficulty of establishing the diagnosis in the absence of newborn screening, even with a heightened index of suspicion.Steroidogenic profiles were obtained for the three affected siblings. The available clinical history of the two affected aunts was retrieved. Genotyping was performed on several members of the kindred. Detailed sequencing of the entire CYP21 gene of two clinically dissimilar subjects in this family was undertaken to explore the possibility of other mutations or polymorphisms.PCR with ligase detection reaction analysis of CYP21 revealed that the affected family members III-2, III-3, III-4, II-3, and II-4, all were compound heterozygotes carrying the intron 2 point mutation known to interfere with splicing (nucleotide 656 A to G) and the exon 4 point mutation causing a nonconservative substitution of asparagine for isoleucine at codon 172 (I172N). Detailed sequencing of the gene was performed for the two most phenotypically dissimilar subjects. A single silent polymorphism was found in the third nucleotide for codon 248 in patient II-4, but not in patient III-4, and no additional mutations were found.Classic congenital adrenal hyperplasia remains a difficult diagnosis to make in the absence of newborn screening because of the variability of phenotypic expression. Likewise, the variable degree of genital ambiguity in affected females in this family serves to question universal advocacy of prenatal steroid treatment in pregnancies at risk for congenital adrenal hyperplasia. Extensive molecular exploration did not provide an explanation of the phenotypic heterogeneity and supports the possibility of influences other than the CYP21 gene for the observed divergence.