bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cavernous Sinus Sampling Is Highly Accurate in Distinguishing Cushing’s Disease from the Ectopic Adrenocorticotropin Syndrome and in Predicting Intrapituitary Tumor Location1
Authors: Graham Kathryn E. , Samuels Mary H. , Nesbit Gary M. , Cook David M. , O’Neill Oisin R. , Barnwell Stanley L. , Loriaux D. Lynn 
Published: January 2014

Inferior petrosal sinus sampling (IPSS) is used to distinguish pituitary Cushing’s disease from occult cases of the ectopic ACTH syndrome, but is limited in that it requires the use of ovine CRH (oCRH) and is not highly accurate at predicting the intrapituitary location of tumors. This study was designed to determine whether cavernous sinus sampling (CSS) is as safe and accurate as IPSS, whether CSS can eliminate the need for oCRH stimulation, and whether CSS can accurately predict the intrapituitary location of tumors.
Ninety-three consecutive patients with ACTH-dependent Cushing’s syndrome were prospectively studied with bilateral, simultaneous CSS before and after oCRH stimulation. Prediction of a pituitary or ectopic ACTH source was based on cavernous/peripheral plasma ACTH ratios. Intrapituitary tumor location was predicted based on lateralization (side to side) ACTH ratios. These predictions were compared to surgical outcome in the 70 patients who had surgically proven pituitary (n= 65) or ectopic (n = 5) disease.
CSS distinguished pituitary Cushing’s disease from the ectopic ACTH syndrome in 93% of patients with proven tumors before oCRH administration and in 100% of patients with proven tumors after oCRH. It was as safe and efficacious as published IPSS results. CSS accurately predicted the intrapituitary lateralization of the tumor in 83% of all patients and 89% of those patients with good catheter position and symmetric venous flow.
CSS is as safe and accurate as IPSS for distinguishing patients with pituitary Cushing’s disease from those with the ectopic ACTH syndrome. In addition, CSS appears to be superior to IPSS for predicting intrapituitary tumor lateralization.
Cortisolemic Indices Predict Severe Infections in Cushing Syndrome Due to Ectopic Production of Adrenocorticotropin1
Authors: Sarlis Nicholas J. , Chanock Stephen J. , Nieman Lynnette K. 
Published: January 2014

Because high circulating levels of glucocorticoids impair immunity and predispose to infections, we evaluated whether indices of cortisol (F) production could predict infections in patients with Cushing syndrome (CS) caused by ectopic production of ACTH (EA).
Charts of 54 consecutive patients with untreated EA, without underlying diagnosis of small cell carcinoma of the lung, were reviewed, and types of infections, white blood cell (WBC) count, fever, as well as the glucocorticoid indices [0800 h F, daily urine F excretion (UFC), and daily urine 17-hydroxysteroid/g creatinine excretion (17OHS)], were recorded.
Thirty-five patients had no or clinically mild infection; the remaining 19 patients had severe, systemic infection (n = 13) and/or sepsis (n = 6), including either bacterial or opportunistic pathogens or both (73.7%, 42.1%, and 13.8%, respectively). The latter group of patients had significantly higher indices of hypercortisolism (F, UFC, and 17OHS) than those with mild or no infections, but these indices did not correlate with temperature or WBC count. Thresholds for identifying severe infection were selected for maximal positive predictive value and were: F, 43.1 μg/dL; UFC, 2000 μg/day; and 17OHS, 35 mg/g creatinine. The most accurate discriminator for severe infection was 17OHS, based on a positive predictive value of 64.7%.
Our data strongly suggests that the likelihood for a bacterial or opportunistic infection in CS patients, even without underlying small cell carcinoma of the lung, is greatest in patients with extreme hypercortisolism. The predictive value of total WBC count or the presence of an elevated temperature is not sufficient to identify patients with severe, life-threatening infection.
Short-Term Fasting Selectively Suppresses Leptin Pulse Mass and 24-Hour Rhythmic Leptin Release in Healthy Midluteal Phase Women without Disturbing Leptin Pulse Frequency or Its Entropy Control (Pattern Orderliness)1
Authors: Bergendahl M. , Iranmanesh A. , Evans W. S. , Veldhuis J. D. 
Published: January 2014

Nutritional signals strongly regulate neuroendocrine axes, such as those subserving release of LH, GH, and TSH, presumptively in part via the adipocyte-derived neuroactive peptide leptin. In turn, leptin release is controlled by both acute (fasting) and long-term (adipose store) nutrient status. Here, we investigate the neuroendocrine impact of short-term (2.5-day) fasting on leptin release in healthy young women studied in the steroid-replete midluteal phase of the normal menstrual cycle. Eight women each underwent 24-h blood sampling at 10-min intervals during a randomly ordered 2.5-day fasting vs. fed session in separate menstrual cycles. Pulsatile leptin release was quantified by model-free Cluster analysis, the orderliness of leptin patterns by the approximate entropy statistic, and nyctohemeral leptin rhythmicity by cosinor analysis. Mean (24-h) serum leptin concentrations fell by 4.6-fold during fasting; namely, from 15.2 ± 2.3 to 3.4 ± 0.6 μg/L (P= 0.0007). Cluster analysis identified 13.9 ± 1.1 and 14.3± 1.1 leptin peaks per 24 h in the fed and fasting states (P = NS), and unchanging leptin interpeak intervals (89 ± 5.4 vs. 92 ± 5.3 min). Leptin peak area declined by 4.2-fold (155 ± 21 vs. 37 ± 7 area units, P = 0.004), due to a reduction in incremental leptin pulse amplitude (4.4 ± 0.7 vs. 1.0 ± 0.13 μg/L, P = 0.0011). The cosine amplitude and mesor (mean) of the 24-h leptin rhythm decreased by 4-fold, whereas the acrophase (timing of the nyctohemeral leptin peak) remained fixed. The approximate entropy of leptin release was stable, thus indicating preserved orderliness of leptin release patterns in fasting. Cross-correlation analysis revealed both positive (fed) and negative (fasting) leptin-GH relationships, but no leptin-LH correlations.
In summary, short-term (2.5-day) fasting profoundly suppresses 24-h serum leptin concentrations and pulsatile leptin release in the sex steroid-sufficient midluteal phase of healthy women via mechanisms that selectively attenuate leptin pulse area and incremental amplitude. In contrast, the pulse-generating, nyctohemeral phase-determining, and entropy-control mechanisms that govern 24-h leptin release are not altered by acute nutrient restriction at this menstrual phase. Leptin-GH (but not leptin-LH) showed nutrient-dependent positive (fed) and negative (fasting) cross-correlations. Whether similar neuroendocrine mechanisms supervise altered leptin signaling during short-term nutrient restriction in men, children, or postmenopausal women is not known.
No Evidence for Linkage at Candidate Type 2 Diabetes Susceptibility Loci on Chromosomes 12 and 20 in United Kingdom Caucasians
Authors: Frayling Timothy M. , McCarthy Mark I. , Walker Mark , Levy Jonathan C. , O’Rahilly Stephen , Hitman Graham A. , Subba Rao Pamidighantam V. , Bennett Amanda J. , Jones Elizabeth C. , Menzel Stephan , Ellard Sian , Hattersley Andrew T. 
Published: January 2014

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1α (HNF-1α) and HNF-4α. Two studies examining the HNF-1α region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4α locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs.
A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1α and HNF-4α regions, respectively.
We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.
Estrogen Receptor Isoform Gene Expression in Ovarian Stromal and Epithelial Tumors*
Authors: Chu Simon , Mamers Pam , Burger Henry G. , Fuller Peter J. 
Published: January 2014

AbstractThe factors involved in the pathogenesis of ovarian cancers remain unclear, and the response of these tumors to hormonal therapy is limited. The identification of a second estrogen receptor gene (ERβ), expressed predominantly in ovarian granulosa cells, led us to explore its possible role in ovarian cancer, particularly in granulosa cell tumors (GCT). Several isoforms of ERβ have been identified. We sought to define the patterns of both ERα and ERβ gene expression in a panel of ovarian tumors consisting of GCT and serous and mucinous cystadenocarcinomas as well as in normal ovary. Expression was determined by RT-PCR using gene- and isoform-specific primers and probes combined with Southern blot analysis of the PCR products. Widespread expression of ERα was observed in all tumor types, but at relatively low levels. ERβ is expressed predominantly in GCT, with lower levels in mucinous tumors and very low levels in serous tumors. The ERβ2 splice variant previously reported in rodents was not observed. Only very low levels of the exon 5, exon 6, and exon 5/6 deletion variants were detected. The C-terminal truncation variant ERβcx, however, exhibited widespread expression across all the tumor types. As ERβcx has been shown to be a ligand-independent antagonist of ERα action, the relative ratios of ERβcx, ERα, and ERβ may influence the response of a tumor to antiestrogen therapy.
Significance of Pro12Ala Mutation in Peroxisome Proliferator-Activated Receptor-γ2 in Korean Diabetic and Obese Subjects*
Authors: Oh Eun Young , Min Kyeong Min , Chung Jae Hoon , Min Yong-Ki , Lee Myung-Shik , Kim Kwang-Won , Lee Moon-Kyu 
Published: January 2014

Abstract
Peroxisome proliferator-activated receptors (PPARs) are a nuclear hormone receptor superfamily of ligand-activated transcription factors, and the PPARγ subtype regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. There have been several reports on the relationship between the PPARγ2 Pro12Ala genotype and obesity or diabetes in Caucasians. The objective of this study was to examine the relationship between this mutation and obesity or diabetes in Korean subjects. Two hundred and twenty-nine Korean subjects, including 111 obese subjects (body mass index, &gt;25 kg/m2) were included in this study. One hundred and eleven subjects had normal glucose tolerance, 60 had impaired glucose tolerance, and 58 had diabetes mellitus. We evaluated these subjects for the Pro12Ala mutation in the PPARγ gene using PCR-restriction fragment length polymorphism. Allele frequencies of the Pro12Ala missense mutation of PPARγ2 were not different among Korean subjects with normal glucose tolerance (qAla = 0.045), those with impaired glucose tolerance (qAla = 0.033), and those with diabetes mellitus (qAla = 0.043; P&gt; 0.05). Allele frequencies of PPARγ2 Ala in obese subjects (qAla = 0.036) were not significantly different from those in nonobese subjects (qAla = 0.047). These results suggest that the Pro12Ala mutation in PPARγ is not associated with either diabetes or obesity and may not be an important determinant of obesity or diabetes in Korean subjects.
Spatio-Temporal Expression of the Trans-Acting Splicing Factors SF2/ASF and Heterogeneous Ribonuclear Proteins A1/A1B in the Myometrium of the Pregnant Human Uterus: A Molecular Mechanism for Regulating Regional Protein Isoform Expression in Vivo*
Authors: Pollard Alison J. , Sparey Colette , Robson Stephen C. , Krainer Adrian R. , Europe-Finner G. Nicholas 
Published: January 2014

Abstract
Many of the human myometrial proteins associated with uterine quiescence and the switch to coordinated contractions at the onset of labor exist as alternatively spliced isoforms. There is now extensive evidence to indicate that the nuclear concentrations of the trans-acting splicing regulators SF2/ASF and hnRNP A1/A1B are fundamental in regulating the expression of specific protein isoforms derived from alternative splicing of single precursor messenger ribonucleic acid transcripts. The question thus arose as to whether these factors were also involved in regulating the expression of specific myometrial protein species within different uterine regions during human gestation and parturition. SF2/ASF and hnRNP A1/A1B expression was therefore determined in paired upper (corpus) and lower segment myometrial samples taken from individual women at term/during spontaneous labor and compared with nonpregnant control samples using specific monoclonal antibodies. We report that SF2/ASF levels were substantially increased in the lower uterine region, and this was associated with a parallel decrease in levels of hnRNP A1/A1B during gestation. Conversely, the opposite pattern was observed within the upper uterine region during pregnancy, where hnRNP A1/A1B was significantly up-regulated and SF2/ASF levels were much less than those found in the lower uterine segment. The differential expression of hnRNP A1/A1B and SF2/ASF in the upper and lower uterine segments may have a primary role in defining the formation of specific myometrial protein species associated with the known contractile and relaxatory properties of these regions before and during parturition.
Preserved Male Fertility Despite Decreased Androgen Sensitivity Caused by a Mutation in the Ligand-Binding Domain of the Androgen Receptor Gene1
Authors: Giwercman Aleksander , Kledal Thomas , Schwartz Marianne , Giwercman Yvonne Lundberg , Leffers Henrik , Zazzi Henric , Wedell Anna , Skakkebæk Niels E. 
Published: January 2014

Mutations in the androgen receptor gene are considered as incompatible with preservation of fertility and have been suggested as a cause of male infertility.Two adult brothers, referred because of gynecomastia and hormonal levels in serum indicating androgen insensitivity (high sex hormone-binding globulin, and LH levels, despite extremely high testosterone concentration), turned out to be relatives to a third young man, referred independently of the two others and exhibiting identical clinical and hormonal stigmata. In all three men, we found a C→A substitution at position 2470 (exon 7) in the androgen receptor gene, leading to a Gln824Lys mutation in the ligand-binding domain of the receptor. Exploring the family history revealed that their grandfathers, on their mothers’ side, were brothers; and the Gln824Lys mutation was also found in the one of them who was still alive.Binding studies with the mutant receptor in transfected COS-7 cells, with mibolerone as ligand, exhibited equal Kd (0.7 vs. 1.0 nmol/L), IC50 (0.8 vs. 1.1 nmol/L), and maximum binding (7.1 vs. 8.9 fmol/106 cells), as compared with the wild-type (WT) receptor. In a chloramphenicol acetyl transferase trans-activation assay, the activity of the mutant receptor was identical to that of the WT, when the synthetic androgen R1881 was used as a ligand; but with dihydrotestosterone, in concentrations up to 10 nmol/L, the activity of Gln824Lys mutated receptor was 10–62% of the WT variant.Thus, Gln824Lys mutation was found, both in vivo and in vitro, to cause slight impairment of receptor function but was compatible with preservation of male fertility. The patients inherited the mutation from their grandfathers through their mothers, and one of the young men possessing the mutation has fathered a daughter.
Distribution and Abundance of Messenger Ribonucleic Acid for Growth Hormone Receptor Isoforms in Human Tissues1
Authors: Ballesteros Mercedes , Leung Kin-Chuen , Ross Richard J. M. , Iismaa Tiina P. , Ho Ken K. Y. 
Published: January 2014

Two alternatively spliced exon 9 variants of human GH receptor (GHR) messenger ribonucleic acid (mRNA), GHR-(1–279) and GHR-(1–277), were recently identified in liver. They encode receptor proteins lacking most of the intracellular domain and inhibit GH action in a dominant negative manner. Little is known about tissue distribution and abundance of these GHR isoforms. We have developed quantitative RT-PCR assays specific for the full-length and truncated GHRs and investigated their expression in various human tissues and cell lines.
The mRNA of full-length GHR and GHR-(1–279) were readily detectable in all tissues investigated, with liver, fat, muscle, and kidney showing high levels of expression. These two receptor isoforms were also detected in a range of human cell lines, with strongest expression in IM9, a lymphoblastoid cell line. In contrast, GHR-(1–277) message was expressed at low levels in liver, fat, muscle, kidney, and prostate and in trace amount in IM9 cells.
Full-length GHR was the most abundant isoform, accounting for over 90% of total receptor transcripts in liver, fat, and muscle for quantitative RT-PCR. However, liver had 2- to 4-fold more full-length receptor mRNA and 16- to 40-fold more GHR-(1–277) mRNA than fat and muscle, whereas the mRNA levels of GHR-(1–279) were similar in the three tissues. GHR-(1–279) constituted less than 4% in liver and 7–10% in fat and muscle. GHR-(1–277) accounted for 0.5% of total GHR transcripts in liver and less than 0.1% in the other two tissues. These data suggest that the absolute and relative abundance of mRNA of the three GHR isoforms may be tissue specific. The regulation of expression of exon 9 alternatively spliced GHR variants may provide a potential mechanism for modulation of GH sensitivity at the tissue level.
Circulating Insulin-Like Growth Factor II and Colorectal Adenomas*
Authors: Renehan Andrew G. , Painter John E. , O’Halloran Domhnall , Atkin Wendy S. , Potten Christopher S. , O’Dwyer Sarah T. , Shalet Stephen M. 
Published: January 2014

Abstract
Circulating insulin-like growth factor I (IGF-I) and IGF-binding protein-3 (IGFBP-3) may be risk factors for the development of colorectal cancer. On the other hand, IGF-II and IGFBP-2 are overexpressed in colorectal carcinomas. These contrasting backgrounds led us to investigate the relationship between serum IGF-I, IGF-II, IGFBP-2, and IGFBP-3 and the presence of colorectal adenomas, known precursors of colorectal carcinoma, in 345 volunteers attending a screening flexible sigmoidoscopy trial (entry criteria: healthy, aged 55–64 yr). The most striking finding was an elevated mean serum IGF-II in individuals with adenomas (n = 52) compared with controls (mean difference, 139 ng/mL; 95% confidence intervals, 82, 196; P &lt; 0.0001). Logistic regression adjusting for confounding factors confirmed the significant association between IGF-II and adenoma occurrence (P &lt; 0.0001) and revealed an additional positive association with serum IGFBP-2 (P &lt; 0.0001). However, there was no association found between either serum IGF-I and/or IGFBP-3 and the presence of adenomas. Additionally, in 31 individuals with adenomas in whom levels were determined pre- and postpolypectomy, there was a significant fall in mean IGF-II (P &lt; 0.001) and IGFBP-2 (P &lt; 0.001) after adenoma removal, but no difference in IGF-II and IGFBP-2 concentrations between repeated samples in 20 individuals without adenomas. Immunohistochemical studies demonstrated IGF-II expression in 83% of all adenomas, which contrasted with absent expression in normal colonic expression and hyperplastic polyps. This study has shown for the first time that serum IGF-II may be a tumor marker in individuals with colorectal adenomas. Further studies are needed to validate these relationships in larger populations, including individuals undergoing colonoscopy.
Effects of Metyrapone Administration on Thyrotropin Secretion in Healthy Subjects–A Clinical Research Center Study*
Authors: Samuels M. H. 
Published: January 2014

Abstract
Although pharmacological doses of glucocorticoids suppress TSH secretion, less is known regarding the effects of physiological variations in cortisol levels on TSH. To study this issue, 12 healthy subjects each underwent 2 studies, in random order: 1) each subject received an infusion of saline for 48 h; and 2) each subject received an infusion of saline and oral administration of metyrapone (500 mg every 4 h) for 48 h. Cortisol and TSH levels were measured every 15 min during the final 24 h of each study, and resulting mean hormone levels during the 24-h periods were compared between the two studies. Metyrapone administration reduced serum cortisol levels by 39% between 0800 and 1345 h and by 47% between 0200 and 0745 h, with no significant changes during other time periods. Metyrapone increased daytime (0800–1945 h) mean TSH levels by 35%, with no change in nocturnal (2000–0745 h) TSH levels. This led to equalization of daytime and nocturnal TSH levels and abolition of the usual circadian variation in TSH. TSH pulse frequency was no different between the two studies, whereas daytime TSH pulse amplitude increased 33% during metyrapone administration. There were no changes in TSH responses to TRH, or in serum T3 or free T4 levels, at the end of the studies. These results suggest that the early morning increase in endogenous cortisol levels in healthy subjects causes the daytime decrease in TSH levels. In addition, these results show that very mild changes in cortisol levels within the physiological range are sufficient to affect TSH secretion.