bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gestational and Lactational Exposure of Male Mice to Diethylstilbestrol Causes Long-Term Effects on the Testis, Sperm Fertilizing Ability in Vitro, and Testicular Gene Expression
Authors: Fielden Mark R. , Halgren Robert G. , Fong Cora J. , Staub Christophe , Johnson Larry , Chou Karen , Zacharewski Tim R. 
Published: January 2014

AbstractThe objective of the study was to determine the long-term effects of gestational and lactational exposure to diethylstilbestrol (DES; 0, 0.1, 1, and 10 μg/kg maternal body weight) on mouse testicular growth, epididymal sperm count, in vitro fertilizing ability, and testicular gene expression using cDNA microarrays and real-time PCR in mice on postnatal day (PND) 21, 105, and 315. In the high dose group there was a persistent decrease in the number of Sertoli cells, and sperm count was decreased on PND315 (P &lt; 0.05). Sperm motion was unaffected; however, the in vitro fertilizing ability of epididymal sperm was decreased in the high dose group on both PND105 (P &lt; 0.001) and PND315 (P &lt; 0.05). Early and latent alterations in the expression of genes involved in estrogen signaling (estrogen receptor α), steroidogenesis (steroidogenic factor 1, 17α-hydroxylase/C17,20-lyase, P450 side chain cleavage, steroidogenic acute regulatory protein, and scavenger receptor class B1), lysosomal function (LGP85 and prosaposin), and regulation of testicular development (testicular receptor 2, inhibin/activin β C, and Hoxa10) were confirmed by real-time PCR. The results demonstrate that early exposure to DES causes long-term adverse effects on testicular development and sperm function, and these effects are associated with changes in testicular gene expression, even long after the cessation of DES exposure.
Allelic Deletion in Pituitary Adenomas Reflects Aggressive Biological Activity and Has Potential Value as a Prognostic Marker1
Authors: Bates A. S. , Farrell W. E. , Bicknell E. J. , McNicol A. M. , Talbot A. J. , Broome J. C. , Perrett C. W. , Thakker R. V. , Clayton R. N. 
Published: January 2014

Abstract
Tumors of the pituitary gland are usually benign adenomas and account for 10% of all intracranial neoplasms. Five pituitary tumors have previously been reported to harbor multiple allelic deletions. Of these, three displayed particularly aggressive biological behavior, whereas there were no clinical details provided for the others. This study was designed to test the hypothesis that genetic deletions are a marker of invasive behavior and to identify the loci most commonly involved. Accordingly, we studied two cohorts of pituitary tumors, classified radiologically as invasive or noninvasive, for loss of heterozygosity (LOH).
There is a significantly higher frequency of LOH in invasive tumors (10.8% of all loci examined) compared to noninvasive tumors (2.4%; P &lt; 0.001). Of the 11 loci investigated, 75% of the allelic deletions identified in invasive tumors were found at 4 loci: 11q13, 13q12–14, 10q, and 1p. Twenty of 47 invasive tumors had evidence of at least 1 allelic deletion, whereas 14 of 20 had more than 1. Of the 6 tumors with only 1 deletion, 5 involved the 11q13 locus, suggesting that this is an early change in the transition from noninvasive to invasive adenoma. Comparison of invasive and noninvasive tumors demonstrates a significantly higher frequency of deletions affecting 11q13 (P &lt; 0.001), 13q12–14 (P &lt; 0.05), and 10q26 (P &lt; 0.05) in invasive tumors. In addition, allelic deletion correlates with increasingly invasive behavior (modified Hardy classification), as 73% of grade 4 tumors compared to 33% of grade 3 and 9.5% of grade 1 and 2 tumors demonstrated LOH at any locus. Furthermore, in some tumors we identified a breakpoint between markers intragenic and extragenic to the retinoblastoma gene (Rb1) on chromosome 13q, suggesting that tumor suppressor genes other than or in addition to Rb1 may be involved in pituitary tumorigenesis. This was further supported by the presence of Rb protein in two of four tumors where the genetic loss extended to include the intragenic marker D13S153.
Early identification of tumors with likely invasive potential by means of genetic analysis (LOH) may provide useful information on potential tumor behavior and aid tumor management in a manner that is not possible using routine histological methods. A large prospective study is required in patients without radiological evidence of invasion to assess the value of LOH in predicting outcome and for planning treatment.
Direct Postoperative and Follow-Up Results of Transsphenoidal Surgery in 19 Acromegalic Patients Pretreated with Octreotide Compared to Those in Untreated Matched Controls
Authors: Biermasz N. R. , van Dulken H. , Roelfsema F. 
Published: January 2014

Abstract
In this study 19 patients were preoperatively treated with octreotide for 1–17 months (mean, 5 months), with doses from 150–1500 μg daily, and those patients were matched to 19 untreated patients with comparable tumor classification and preoperative serum GH concentrations. Octreotide was started at 300 μg daily by sc injections or continuous sc infusion using a pump in increasing doses, depending on the responses of the serum GH and insulin-like growth factor I (IGF-I) concentrations. During pretreatment, seven patients achieved a serum GH concentration below 5 mU/L, whereas six patients normalized their serum IGF-I.
Postoperatively, a serum GH concentration below 5 mU/L was achieved in 15 pretreated and 14 untreated patients, a normal serum IGF-I level (&lt;2 sd) was achieved in 10 pretreated and 15 untreated patients, and normal serum GH suppression during GTT was reached in 12 treated and 14 control patients. No differences were found in complication rate or incidence of hypopituitarism caused by surgery.
Adjuvant therapy was required in 7 treated and 5 untreated patients. At follow-up examination, 5.7 and 4 yr postoperatively, 10 pretreated and 12 control patients could be considered cured by surgery only, according to our criteria for remission (serum GH, &lt;5 mU/L; normal GH suppression and normal serum IGF-Ι). In summary, we found no difference in direct postoperative and follow-up results of transsphenoidal surgery between pretreated patients and untreated patients. This finding is in discordance with other studies, which have claimed a beneficial effect of octreotide pretreatment.
Differentiation of Human Orbital Preadipocyte Fibroblasts Induces Expression of Functional Thyrotropin Receptor1
Authors: Valyasevi Rosanee W. , Erickson Dana Z. , Harteneck Debra A. , Dutton Charyl M. , Heufelder Armin E. , Jyonouchi Soma C. , Bahn Rebecca S. 
Published: January 2014

Although the autoantigen involved in Graves’ hyperthyroidism is known to be the TSH receptor (TSHr), whether this antigen plays a primary role in the pathogenesis of Graves’ ophthalmopathy (GO) is unclear. We sought to determine whether fibroblasts derived from orbital adipose/connective tissue are capable of differentiating into adipocytes that bear immunoreactive and functional TSHr. In addition, we assessed relative levels of TSHr gene expression in normal and GO orbital adipose/connective tissue specimens.GO and normal orbital preadipocyte fibroblasts, cultured under conditions known to stimulate adipocyte differentiation, showed evidence of adipogenesis and positive immunostaining for TSHr protein. In addition, significantly more cAMP was produced in response to TSH stimulation in the differentiated cultures than in undifferentiated cultures derived from the same individuals’ cells. Other studies demonstrated relatively greater TSHr gene expression in GO than in normal orbital tissue specimens.These results indicate that orbital preadipocyte fibroblasts increase their TSHr expression with differentiation and suggest that these cells play an important role in the pathogenesis of GO. Furthermore, our studies support the concept that TSHr may be an important target antigen in this condition. Factors that stimulate adipocyte differentiation and TSHr expression in the orbit in GO have yet to be defined.
Somatostatin Receptor Subtypes in Human Thymoma and Inhibition of Cell Proliferation by Octreotide in Vitro
Authors: Ferone Diego , van Hagen Martin P. , Kwekkeboom Dik J. , van Koetsveld Peter M. , Mooy Diana M. , Lichtenauer-Kaligis Elgin , Schönbrunn Agnes , Colao Annamaria , Lamberts Steven W. J. , Hofland Leo J. 
Published: January 2014

Somatostatin (SS) and SS receptor (SSR) subtypes, code-named sst1–5, are heterogeneously expressed in the normal human thymus. This suggests their involvement in controlling the immune and/or neuroendocrine functions in this organ. Moreover, recently a high in vivo uptake of[ 111In-DTPA-d-Phe1]octreotide has been reported in patients bearing thymoma. The present study characterizes in vivo and in vitro, functional SS-binding sites in a human thymoma.
A high uptake of[ 111In-DTPA-d-Phe1]octreotide was observed in the chest of a patient with myasthenia gravis due to a cortical thymoma. Specific binding of[ 125I-Tyr11]SS-14 was found on a membrane preparation of the surgically removed thymoma. Scatchard analysis showed high affinity binding sites (Kd, 47.5 ± 2.5 pmol/L) with low maximum binding capacity (23.5 ± 2.5 fmol/mg membrane protein). RT-PCR analysis showed the presence of sst1, sst2A, and a predominant sst3 messenger RNA (mRNA) expression in the tumor tissue. Primary cultured tumor cells expressed sst3 mRNA only. In contrast to the normal thymus, SS mRNA was not expressed. By immunohistochemistry, the tumor cells highly expressed sst3 receptors, weakly expressed sst1 receptors, and showed no immunostaining for sst2A receptors. sst2A immunoreactivity was found in the stromal compartment of the tumor, particularly on the endothelium of small intratumoral blood vessels. In primary cultured tumor cells, both SS and octreotide (10 nmol/L) significantly inhibited[ 3H]thymidine incorporation by 40.6% and 43.2%, respectively.
The following conclusions were reached. 1) As this tumor displayed a high immunoreactivity for sst3 and the cultured tumor cells expressed the sst3 mRNA only, this SSR may be the subtype involved in the inhibition of epithelial tumor cell proliferation by octreotide in vitro. 2) A loss of endogenous SS production in this thymoma might be implicated in the uncontrolled cell growth. 3) In this case, the sst3 may play a role in determining the uptake of[ 111In-DTPA-d-Phe1]octreotide by in vivo SS receptor scintigraphy.
Preeclampsia Is Associated with Low Circulating Levels of Insulin-Like Growth Factor I and 1,25-Dihydroxyvitamin D in Maternal and Umbilical Cord Compartments*
Authors: Halhali Ali , Tovar Armando R. , Torres Nimbe , Bourges Hector , Garabedian Michele , Larrea Fernando 
Published: January 2014

AbstractInsulin-like growth factor I (IGF-I) stimulates renal and placental 1,25-dihydroxyvitamin D [1,25-(OH)2D] and is considered an important regulator of fetal growth. As 1,25-(OH)2D and birth weight are low in preeclampsia, this study was undertaken to determine whether circulating levels of IGF-I were associated with serum 1,25-(OH)2D concentrations in preeclamptic (PE group) and normotensive (NT group) pregnancies. Maternal and umbilical cord serum levels of IGF-I and 1,25-(OH)2D were significantly (P &lt; 0.01) lower in the PE group than in the NT group. The concentrations of these two hormones correlated significantly in the umbilical cord (P &lt; 0.05) and in the maternal (P &lt; 0.001) compartments of the PE and NT groups, respectively. The amount of IGFBP-3 was 64% lower whereas that of IGFBP-1 was 2.9-fold higher in umbilical cord serum of the PE group compared with the NT group. In addition, maternal and umbilical cord serum IGF-I correlated significantly (P &lt; 0.05) with weight and length at birth only in the PE group. In conclusion, the results of this study indicate that circulating IGF-I and 1,25-(OH)2D levels in both maternal and umbilical cord compartments are low in preeclampsia. Furthermore, this study suggests a differential regulatory effect of IGF-I on 1,25-(OH)2D synthesis and fetal growth depending on the presence or absence of preeclampsia.
Continuation of Growth Hormone (GH) Replacement in GH-Deficient Patients during Transition from Childhood to Adulthood: A Two-Year Placebo-Controlled Study
Authors: Vahl Nina , Juul Anders , Jørgensen Jens O. L. , Ørskov Hans , Skakkebæk Niels E. , Christiansen Jens. S. 
Published: January 2014

Abstract
Previous studies have demonstrated beneficial effects of GH replacement, in adults with GH deficiency (GHD), on body composition, physical fitness, and quality of life. These studies, however, concern patients with adult-onset GHD or childhood-onset (CO) patients enrolled several years after withdrawal of initial therapy. So far, the effects of continuation of GH-administration in patients with CO-GHD have not been examined. We studied a group of nineteen young adults (13 males+ 6 females; 16–26 yr old; mean age, 20.2 ± 0.65 yr) with CO-GHD, in a randomized, parallel, double-blind, placebo-controlled trial for 1 yr, followed by an open phase with GH for 1 yr. All patients received GH therapy at the start of study, and trial medication (GH/placebo) was given in a similar dose. Patients randomized to continued GH treatment exhibited no significant changes in any parameters tested, but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems. Discontinuation of GH for 1 yr resulted in a decrease in serum IGF-I, from 422.0 ± 56.8 to 147.8 ± 33.4 μg/L, in the placebo group (P = 0.003). After discontinuation of GH for 1 yr, an increase in total body fat (TBF, kg), measured by dual-energy x-ray absorptiometry scan, was seen[ placebo: 22.7 ± 2.7 to 26.5 ± 2.5 (P = 0.01); GH:16.2 ± 2.1 to 17.2 ± 2.1 (not significant)]. Resumption of GH after placebo was followed by increments in serum IGF-I (μg/L) [from 147.8 ± 33.4 to 452 ± 76 (P = 0.001)] and IGF-binding protein 3, as well as in fasting glucose (mmol/L) [4.9 ± 0.2 vs. 5.3 ± 0.2 (P = 0.03)]. After resumption of GH lean body mass (kg) increased [52.4 ± 4.9 vs. 60.7 ± 5.6 (P = 0.006)]. Likewise, resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio, as assessed by computed tomography [muscle volume (cm2/10 mm): 118.2 ± 11.7 vs. 130.0 ± 10.9 (P = 0.002); muscle/fat ratio: 1.33 ± 0.24 vs. 1.69 ± 0.36 (P = 0.02)].
In conclusion, discontinuation of GH treatment in GHD patients, during the transition from childhood to adulthood, induces significant and potentially unfavorable changes in IGF-I and body composition, both of which are reversed after resumption of GH treatment. By contrast, continuation of GH therapy results in unaltered IGF-I and body composition. We recommend continuation of GH therapy in these patients, to be undertaken in collaboration between pediatricians and adult endocrinologists.
Progesterone Withdrawal Up-Regulates Vascular Endothelial Growth Factor Receptor Type 2 in the Superficial Zone Stroma of the Human and Macaque Endometrium: Potential Relevance to Menstruation*
Authors: Nayak Nihar R. , Critchley Hilary O. D. , Slayden Ov D. , Menrad Andreas , Chwalisz Kristof , Baird David T. , Brenner Robert M. 
Published: January 2014

AbstractSeveral reports indicate that vascular endothelial growth factor (VEGF) expression is increased in endometrial glands and stroma during the menstrual phase in the human endometrium. Here we report that VEGF receptor type 2 (KDR), normally expressed only in the vascular endothelium, was dramatically up-regulated in the stromal cells of the superficial endometrial zones during the premenstrual phase in both human and macaque endometrium. This increase was detectable by Northern analysis, in situ hybridization, and immunocytochemistry and was cell specific, zone specific, cycle phase specific, and VEGF receptor type specific. That is, it only occurred during the premenstrual/menstrual phase, did not occur in glandular epithelium, endothelium, or stromal cells of the deepest endometrial zones, and was not observed for VEGF receptor type 1. The up-regulation of stromal KDR was induced by progesterone (P) withdrawal in both women and macaques, and adding back P 24 h after P withdrawal in macaques blocked stromal, but not vascular, endothelial KDR expression. Promatrix metalloproteinase-1 (MMP-1) was coordinately up-regulated in the same stromal cell population by P withdrawal. Because of reports that VEGF can enhance MMP expression, we hypothesize that VEGF-KDR interactions may influence MMP expression in the superficial zones of the primate endometrium during the premenstrual phase, and that these interactions play a role in the induction of menstruation.
Effects of Soy Isoflavones on Markers of Bone Turnover in Premenopausal and Postmenopausal Women*
Authors: Wangen Kerry E. , Duncan Alison M. , Merz-Demlow Barb E. , Xu Xia , Marcus Robert , Phipps William R. , Kurzer Mindy S. 
Published: January 2014

Abstract
Soy isoflavones are hypothesized to exert hormonal effects in women and thus may play a role in bone metabolism throughout life. In 2 randomized, cross-over studies, 14 pre- and 17 postmenopausal women were given 3 soy protein isolates containing different amounts of isoflavones [control, 0.13; low isoflavone (low-iso), 1.00; and high-iso, 2.01 mg/kg body wt·day, averaging 8, 65, and 130 mg/day, respectively], for over 3 months each. Food records, blood samples, and 24-h urine collections were obtained throughout the studies. The endpoints evaluated included plasma or serum concentrations of bone-specific alkaline phosphatase, osteocalcin, insulin-like growth factor-I (IGFI), IGF binding protein-3 (IGFBP3), and urine concentrations of deoxypyridinoline cross-links and carboxy-terminal telopeptide of type I collagen. In premenopausal women, IGFI and IGFBP3 concentrations were increased by the low-iso diet, and deoxypyridinoline cross-links was increased by both the low- and high-iso diets during certain phases of the menstrual cycle. In postmenopausal women, bone-specific alkaline phosphatase was decreased by both the low- and high-iso diets, and there were trends toward decreased osteocalcin, IGFI, and IGFBP3 concentrations with increasing isoflavone consumption. Although soy isoflavones do affect markers of bone turnover, the changes observed were of small magnitude and not likely to be clinically relevant. These data do not support the hypothesis that dietary isoflavones per se exert beneficial effects on bone turnover in women.
Codon-54 Polymorphism of the Fatty Acid-Binding Protein 2 Gene Is Associated with Elevation of Fasting and Postprandial Triglyceride in Type 2 Diabetes*
Authors: Georgopoulos Angeliki , Aras Omer , Tsai Michael Y. 
Published: January 2014

AbstractPatients with type 2 diabetes are frequently dyslipidemic or hypertriglyceridemic. To assess whether increased intestinal triglyceride input leads to elevated fasting and postprandial triglycerides in type 2 diabetes, we used the codon 54 polymorphism of the fatty acid-binding protein 2 gene, which results in the substitution of threonine (Thr) for alanine and is associated with increased intestinal input of triglyceride. Of the 287 diabetic patients screened, 108 (37.6%) were heterozygous and 31 (10.8%) were homozygous for the Thr-54 allele. Mean (±sem) fasting plasma triglyceride levels in patients with the wild-type (n = 80), those heterozygous for the Thr-54 allele (n = 57), and those homozygous for it (n = 18) were 2.0 ± 0.09, 2.7 ± 0.20, and 3.8 ± 0.43 mmol/L, respectively. A linear relationship of mean fasting plasma triglyceride levels (r2 = 0.97) between the 3 groups was found. After fat ingestion, the postprandial area under the curve of plasma triglyceride (P = 0.025) and chylomicrons (Sf &gt; 400, P = 0.013) was higher in the Thr-54/Thr-54 (n = 6) than in the wild-type (n= 9). Our results are consistent with the hypothesis that, in type 2 diabetes, increased intestinal input of triglyceride can lead to elevated fasting and postprandial plasma triglycerides.
Effects of Octreotide Treatment on the Proliferation and Apoptotic Index of GH-Secreting Pituitary Adenomas
Authors: Losa Marco , Ciccarelli Enrica , Mortini Pietro , Barzaghi Raffaella , Gaia Daniela , Faccani Giuliano , Papotti Mauro , Mangili Francesca , Terreni Maria Rosa , Camanni Franco , Giovanelli Massimo 
Published: January 2014

To investigate the effects of octreotide administration on the growth rate of GH-secreting pituitary adenomas, we measured both the Ki-67 labeling index (LI) and the apoptotic index in tumor specimens from octreotide-treated or matched untreated acromegalic patients. Thirty-nine patients who received octreotide until the day of or the day before surgery and 39 untreated patients matched for sex, age, tumor size, extension, and invasiveness were studied. Immunocytochemical analysis was performed on paraffin-embedded material using a monoclonal antibody (MIB-1) directed against a proliferation-associated nuclear antigen, Ki-67, to measure the growth fraction. Apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick endlabeling method, using a monoclonal antibody recognizing areas of DNA fragmentation. The Ki-67 LI and apoptosis were counted on separate slides in at least 1000 evaluable cells.
Octreotide-treated patients showed a lower Ki-67 LI (1.8 ± 0.3%) than untreated controls (3.8 ± 0.7%; P &lt; 0.02). Overall, the mean Ki-67 LI of treated patients was 53% lower than that in untreated patients. The antiproliferative effect of octreotide occurred independently of tumor extension and invasiveness. Octreotide-treated and untreated patients showed similar apoptotic indexes (0.6 ± 0.2% and 0.8 ± 0.3%, respectively). There was a positive correlation between the Ki-67 LI and the apoptotic index (r = 0.29; P&lt; 0.03).
Our study demonstrates that acromegalic patients receiving chronic octreotide treatment have a lower value of the proliferation marker Ki-67, but no significant difference in the apoptotic index compared with matched untreated patients. The antiproliferative effect of octreotide on GH-secreting adenomas should imply a lower risk of tumor growth during long-term chronic treatment with the drug.
Phenotypes Associated with SHOX Deficiency
Authors: Ross Judith L. , Scott Charles , Marttila Pia , Kowal Karen , Nass Andrea , Papenhausen Peter , Abboudi Jack , Osterman Lee , Kushner Harvey , Carter Peter , Ezaki Marybeth , Elder Frederick , Wei Fanglin , Chen Huaqun , Zinn Andrew R. 
Published: January 2014

Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3–56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype.
SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from −4.6 to +0.6 sd (mean ± sd = −2.2 ± 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations.
In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.