bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of Growth Hormone (GH) Hypersecretion due to Ectopic GH-Releasing Hormone (GHRH) by a Selective GHRH Antagonist*
Authors: Jaffe Craig A. , DeMott-Friberg Roberta , Frohman Lawrence A. , Barkan Ariel L. 
Published: January 2014

Abstract
We have recently demonstrated that a competitive antagonist of GHRH, (N-Ac-Tyr1,d-Arg2)GHRH-(1–29)NH2 (GHRH-Ant), eliminates nearly all nocturnal GH pulsatility in normal subjects, supporting the hypothesis that GH pulsatility is driven by GHRH. In this study, we compared the effects of every 12 h iv boluses of either GHRH-Ant or saline on 24-h GH profiles in a patient with acromegaly due to a metastatic GHRH-secreting carcinoid tumor. Bolus doses of GHRH-Ant (400 μg/kg, iv) acutely suppressed GH concentration to 30–40% of the pretreatment baseline, and this effect lasted 3–4 h. Administration of GHRH (0.33 μg/kg, iv) bolus resulted in a small rise in GH, and this effect was blocked by GHRH-Ant (400μ g/kg). During saline treatment, the secretory patterns of both GH and ectopic GHRH were pulsatile; however, there was no correlation between changes in plasma GHRH and GH concentrations. This lack of correlation was probably due to the majority of circulating GHRH immunoreactivity consisting of nonbiologically active GHRH fragments. These data support the hypothesis that GH hypersecretion in the ectopic GHRH syndrome requires GHRH receptor occupancy and validates the use of GHRH-Ant to probe the potential involvement of endogenous GHRH in patients with acromegaly due to pituitary somatotropinoma.
Diurnal Variations in Twenty-Four-Hour Energy Expenditure During Growth Hormone Treatment of Adults with Pituitary Deficiency*
Authors: Stenlöf Kaj , Johansson Jan-Ove , Lönn Lars , Sjöström Lars , Bengtsson Bengt-Åke 
Published: January 2014

Abstract
The effects of growth hormone (GH) treatment on 24-h energy expenditure (EE) were studied in a open trial over a period of 4 weeks. Five subjects, four men and one woman, with a history of complete GH deficiency were included. All the subjects were examined on 2 consecutive days on baseline and, thereafter, at six occasions during a period of 1 month (days 1, 2, 5, 8, 15, and 30). The dose of GH was 0.25 U/kg·week, administered sc once a day in the evening.
EE was determined in a chamber for indirect calorimetry. Body composition was determined with dual-energy x-ray absorptiometry and computed tomography using a four-scan technique. Blood samples were examined using well-established RIAs.
During the first 2 weeks, 24-h EE increased by 6 ± 3% (range 1–8%) from 40.9 ± 4.8 to 42.9 ± 4.8 kcal/24 h·kg (P &lt; 0.05), sleeping metabolic rate by 14 ± 3% (range 10–18%) from 28.4 ± 1.9 to 32.9 ± 2.2 kcal/24h·kg (P &lt; 0.001), and basal metabolic rate by 11 ± 7% (range 0–18%) from 29.6 ± 2.4 to 33.3 ± 2.6 kcal/24h·kg (P &lt; 0.05). No change was found in daytime EE. The increase in EE covaried with changes in insulin-like growth factor 1, the free T3/free T4 ratio, insulin-like growth factor-binding protein-3, and the aminoterminal procollagen III peptide but not with changes in body composition.
It is suggested that the stimulating effect of GH on EE occurs gradually during a 2-week period and is only detectable during night and morning hours, when significant levels of GH occur.
Blocking of Central Nervous Mineralocorticoid Receptors Counteracts Inhibition of Pituitary-Adrenal Activity in Human Sleep*
Authors: Born Jan , Steinbach Dirk , Dodt Christoph , Fehm Horst-Lorenz 
Published: January 2014

Abstract
Pituitary-adrenal activity has been found to be inhibited during early nocturnal sleep in humans. This inhibition was supposed to reflect a regulatory influence of hippocampal cells characterized by the expression of mineralocorticoid receptors (MR). Pituitary adrenal responsiveness to bolus injections of CRH (50 μg) was examined in each of nine healthy men on four occasions: CRH was injected either during early nocturnal sleep or at the same time of night while the subject was kept awake. Both of these conditions were run after pretreatment with the selective MR antagonist, canrenoate (2 × 200 mg, 0800 and 1700 h, preceding the experimental night) and after placebo administration. After placebo, sleep reduced ACTH and cortisol secretory responses to CRH to about 65% of the size observed during wakefulness (P &lt; 0.05). After canrenoate, ACTH and cortisol secretory responses during sleep and wakefulness did not differ and were comparable with those obtained in placebo-treated subjects during wakefulness. Compared with placebo, canrenoate also distinctly reduced the time spent in slow-wave sleep (P &lt; 0.005). The findings confirm an inhibition of pituitary-adrenal responsiveness during early sleep. The inhibition disappearance after blockage of MR suggests that sleep exerts this influence via central nervous MR-expressing cells. These cells seem to be simultaneously involved in the generation of slow-wave sleep.
Liddle’s Syndrome: Prospective Genetic Screening and Suppressed Aldosterone Secretion in an Extended Kindred*
Authors: Findling James W. , Raff Hershel , Hansson Joni H. , Lifton Richard P. 
Published: January 2014

Abstract
Liddle’s syndrome is an autosomal dominant form of hypertension that resembles primary hyperaldosteronism, is characterized by the early onset of hypertension with hypokalemia and suppression of both PRA and aldosterone, and is caused by mutations in the carboxyl-terminus of theβ - or γ-subunits of the renal epithelial sodium channel. We describe a kindred (K176) whose distinguishing clinical features were mild hypertension and decreased aldosterone secretion. The index case was a 16-yr-old girl with intermittent mild hypertension and hypokalemia and subnormal PRA, aldosterone, 18-hydroxycorticosterone, and deoxycortisol levels, but normal cortisol/cortisone metabolite ratio and cortisol half-life. A frameshift mutation in the carboxyl-terminus of the β-subunit of the epithelial sodium channel was identified in the index case, establishing the diagnosis of Liddle’s syndrome. Sixteen at-risk relatives of the index case were tested. Seven new subjects were heterozygous for the mutation found in the index case, and two deceased obligate carriers were identified. All genetically affected adult subjects had a history of mild hypertension, and four had a history of hypokalemia. Basal and postcosyntropin plasma aldosterone and urinary aldosterone levels were significantly suppressed in those positive for the mutation. The family demonstrates variability in the severity of hypertension and hypokalemia in this disease, raising the possibility that this disease may be underdiagnosed among patients with essential hypertension.
Lack of Association between the Trp64Arg Mutation in the β3-Adrenergic Receptor Gene and Obesity in Japanese Men: A Longitudinal Analysis
Authors: Nagase Terumasa , Aoki Akira , Yamamoto Michiko , Yasuda Hiroko , Kado Seijiro , Nishikawa Miyuki , Kugai Nobuo , Akatsu Takuhiko , Nagata Naokazu 
Published: January 2014

AbstractThe β3-adrenergic receptor (β3AR) is implicated in the regulation of thermogenesis and lipolysis, and it is suggested that the Trp64Arg mutation in this receptor may contribute to the development of obesity. To examine whether the Trp64Arg mutation had any effect on body weight during adult life, the β3AR genotype was determined in 186 unselected Japanese men, most of whom had records of body weight measured yearly from 25–53 yr of age. Of them, 26 subjects were diagnosed as having noninsulin-dependent diabetes mellitus (NIDDM) and 41 as having impaired glucose tolerance. There were 6 subjects (3%) with homozygous mutation, 67 (36%) with heterozygous mutation, and 113 (61%) with normal allele. Among the 3 genotypes, there were no significant differences in body mass index (BMI) at any age between 25–53 yr and the prevalence of NIDDM at the age of 53 yr. When longitudinal changes in body weight were compared between subjects with and without mutation, the former were less prone to gain weight than the latter. The frequency of the mutant allele was 1) not different among obese (BMI, &gt;26.4), intermediate (BMI, 22–26.4), and nonobese (BMI, &lt;22.0) subjects (0.21, 0.22, and 0.26, respectively; P = 0.77); 2) lower in subjects with NIDDM than in those without it, but the difference was insignificant (0.12 vs. 0.23; P = 0.07); and 3) similar between 186 unselected men and another group of 100 patients with NIDDM that were randomly selected for comparison (0.21 vs. 0.23). These results suggest that the β3AR is not a major contributing factor to obesity or NIDDM in Japanese men.
Loss of Heterozygosity at 11q13: Analysis of Pituitary Tumors, Lung Carcinoids, Lipomas, and Other Uncommon Tumors in Subjects with Familial Multiple Endocrine Neoplasia Type 1
Authors: Dong Qihan , Debelenko Larisa V. , Chandrasekharappa Settara C. , Emmert-Buck Michael R. , Zhuang Zhengping , Guru Siradanahalli C. , Manickam Pachiappan , Skarulis Monica , Lubensky Irina A. , Liotta Lance A. , Collins Francis S. , Marx Stephen J. , Spiegel Allen M. 
Published: January 2014

Abstract
Loss of heterozygosity (LOH) for polymorphic markers flanking the multiple endocrine neoplasia type 1 (MEN-1) gene in parathyroid and pancreatic islet tumors from subjects with familial MEN-1 (FMEN-1) has been well documented and has led to the hypothesis that the MEN-1 gene functions as a tumor suppressor. To assess the role of the MEN-1 gene in the pathogenesis of tumors less commonly associated with MEN-1, we employed a large number of highly informative polymorphic markers closely linked to the MEN-1 gene to study a series of 13 such tumors from subjects with FMEN-1 for LOH at 11q13. We were able to identify LOH for 1 or more 11q13 markers in 2 of 3 pituitary tumors, 3 lung carcinoids, and 1 of 2 lipomas. In every case studied, the allele lost represented the normal allele inherited from the unaffected parent. No LOH was detected in 3 skin angiofibromas, an esophageal leiomyoma, or a renal angiomyolipoma despite the presence of at least 2 informative markers for each tumor. Our results suggest that, like that for parathyroid and pancreatic islet tumors, the pathogenesis of pituitary tumors, lung carcinoids, and lipomas occurring in subjects with FMEN-1 probably involves loss of the normal tumor suppressor function of the MEN-1 gene. Our inability to detect 11q13 LOH in skin angiofibromas, leiomyoma, and angiomyolipoma from subjects with FMEN-1 is consistent with the possibility that these neoplasms arose independently by a mechanism unrelated to the MEN-1 gene, but a role for the MEN-1 gene in the pathogenesis of these tumors cannot be definitively excluded until the gene itself is identified and evaluated for small intragenic deletions or point mutations in such tumors.
Assessment of Androgen Receptor Function in Genital Skin Fibroblasts Using a Recombinant Adenovirus to Deliver an Androgen-Responsive Reporter Gene1
Authors: McPhaul Michael J. , Schweikert Hans-Udo , Allman Diane R. 
Published: January 2014

AbstractMutations of the androgen receptor (AR) cause defects in virilization and can result in a spectrum of phenotypic abnormalities of male sexual development that includes patients with a completely female phenotype (complete testicular feminization) and individuals with less severe defects of virilization, such as Reifenstein syndrome. These phenotypes are not specific for mutations of the AR gene, however, and defects in other genes can also result in similar abnormalities of male development. For this reason, the diagnosis of an AR defect is laborious and requires data from endocrine studies, the family history, and in vitro binding experiments.To assist in the evaluation of patients with possible AR defects, we previously employed the use of a recombinant adenovirus to deliver an androgen-responsive gene into fibroblast cultures to assay AR function in normal subjects and patients with complete forms of androgen resistance. Although these studies demonstrated measurable differences between these two groups of subjects, we did not assay samples from patients with partial defects of androgen action. In the current study, we have modified this method to examine AR function in three groups of patients with known or suspected defects of AR function: patients with Reifenstein syndrome, patients with spinobulbar muscular atrophy, and patients with severe forms of isolated hypospadias. When assayed using this method, the AR function of patients with Reifenstein syndrome was intermediate between that of normal control subjects and that of patients with complete testicular feminization. Using the parameters established by the aforementioned experiments, we found that defective AR function can be detected in fibroblasts established from patients with spinobulbar muscular atrophy and in some patients with severe forms of isolated hypospadias, including two with a normal AR gene sequence. These results suggest that this method may have some utility in screening samples to detect defects of AR function, particularly when viewed in the context of other AR assays results.
Alterations in the Glucose-Stimulated Insulin Secretory Dose-Response Curve and in Insulin Clearance in Nondiabetic Insulin-Resistant Individuals
Authors: Jones Clare N. O. , Pei Dee , Staris Patricia , Polonsky Kenneth S. , Chen Y. D.-Ida , Reaven Gerald M. 
Published: January 2014

Abstract
Plasma glucose and insulin responses to a graded iv infusion of glucose were compared in two groups of glucose-tolerant women divided on the basis of their insulin sensitivity. Resistance to insulin-mediated glucose disposal was measured using the insulin suppression test, and the women studied were chosen to represent the highest and lowest quartiles of insulin resistance seen in the normal population. The sensitivity of the pancreatic β-cell to glucose was assessed by measuring the glucose, insulin, and C peptide concentrations in response to continuous graded iv infusions of glucose at rates of 1, 2, 3, 4, 6, and 8 mg/kg·min for 40 min each. In addition, insulin secretion rates in response to the graded glucose infusion, calculated over each sampling period, were derived from deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance. Although plasma glucose concentrations were only slightly higher throughout the glucose infusion, the insulin concentrations were approximately doubled in the insulin-resistant subjects. When expressed as a function of the molar increments in plasma glucose achieved during the glucose infusion studies, the insulin-resistant women had a 90% higher (684 ± 55 vs. 360 ± 36 pmol/L·mmol/L; P &lt; 0.001) total integrated plasma insulin response as the glucose concentration was increased from 5 to 9 mmol/L. However, the total integrated insulin secretory rate was only increased by 37% (1494 ± 133 vs. 1093 ± 125 pmol/mmol/L·min; P &lt; 0.05) in the insulin-resistant group. This discrepancy suggested that insulin clearance was lower in the insulin-resistant subjects, and the calculation of this value, as the ratio of the total secretion of insulin to the area under the plasma insulin curve, was significantly lower in the insulin-resistant group (1.25 ± 0.05 vs. 1.87 ± 0.16 L/min·m2; P &lt; 0.005). These results show that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as a decrease in insulin clearance.
Predictors of Early Remission of Hyperthyroidism in Children1
Authors: Glaser Nicole S. , Styne Dennis M. 
Published: January 2014

AbstractChildren with hyperthyroidism often require prolonged courses of antithyroid medication to achieve remission, and long-term compliance is problematic. To determine which clinical and laboratory features predict early remission, we reviewed the records of 191 patients less than 19 yr old with Graves’ disease. We compared patients achieving remission within 2 yr (group 1, n = 27) with those who completed more than 2 yr of medical therapy but did not achieve a remission (group 2, n = 79). Patients who were in neither of the above categories (n = 85) were excluded from the statistical analysis. Variables that were measurable at the time of diagnosis, recorded in more than 50% of the study population and associated with early remission in the univariate analysis (P ≤ 0.05), were entered into a stepwise multiple logistic regression analysis. Variables retaining a significant association with early remission (P &lt; 0.05) were considered independent predictors of early remission. Patients achieving early remission were older (mean, 12.5 vs. 10.9 yr, P = 0.039) and had higher body mass indexes (BMI, 19.0 vs. 16.6, P = 0.002), higher BMI sd scores (−0.03 vs. −0.60, P = 0.004), lower heart rates (110 vs. 121, P = 0.023), smaller goiters (group 1: 60% with moderate/large goiter; group 2: 83%, P = 0.050), lower platelet counts (272 vs. 339 K/μL, P = 0.006), lower serum T4 and T3 concentrations at presentation (T4: 18.3 vs. 22.5 μg/dL, P = 0.015; T3: 439 vs. 613 ng/dL, P = 0.008), and were less likely to have a positive test for thyroid stimulating Igs (group 1: 50% vs. group 2: 93%, P = 0.008). Regression analysis identified BMI sd score and goiter size as independent predictors of early remission (P &lt; 0.05). Eighty-six percent of patients with BMI sd score above −0.5 sd and minimal/small goiters achieved early remission, compared with 13% of those with BMI sd score below −0.5 sd and moderate/large goiters. We conclude that, of multiple clinical and laboratory variables associated with early remission, BMI sd score and goiter size are independent predictors. Algorithms employing these two variables can be used to facilitate counseling of patients and expedite therapeutic decisions.
The Predictive Value of Biochemical Markers of Bone Turnover for Bone Mineral Density in Early Postmenopausal Women Treated with Hormone Replacement or Calcium Supplementation1
Authors: Rosen Clifford J. , Chesnut Charles H. , Mallinak Nancy J. S. 
Published: January 2014

Abstract
To compare the relative sensitivity and specificity of bone turnover indexes for bone loss or gain in early postmenopausal women, we performed a multicenter trial in 236 menopausal women (mean age, 51 yr), who were randomized to hormone replacement therapy (HRT) or calcium supplementation (CS; 500 mg/day) for 1 yr. Two markers of bone formation, osteocalcin (OC) and bone alkaline phosphatase (BSAP), and two markers of bone resorption, urinary N-telopeptide (NTx) and urinary free deoxypyridinoline (fDpd), as well as spine and femoral neck bone mineral density (BMD) were measured at baseline and 3, 6, and 12 months after treatment. Women receiving HRT (n = 105) showed a significant increase in spine BMD (+2.5%; P &lt; 0.0001) and hip BMD (+1.0%; P = 0.02) compared to women receiving CS, who showed a decline at both sites (−1.1%; P &lt; 0.01). All four markers showed time-dependent decreases in women receiving HRT (P &lt; 0.001) and no change in women receiving CS alone. When baseline indexes of turnover were stratified by quartile, there was a significantly greater increase in BMD among those with the highest NTx, OC, and BSAP levels compared to that in those with the lowest NTx, OC, and BSAP levels (P &lt; 0.05). The highest quartile for percent change from baseline to 6 months in fDpd, BSAP, and NTx was also associated with the greatest change in spine BMD at 1 yr. Receiver operator characteristic curves for percent change from baseline to 6 months in an individual marker to 1 yr change in BMD during HRT revealed that the percent change in NTx provided the greatest discrimination between gain and loss of BMD. When subjects receiving HRT were compared by their positive or negative skeletal response at 1 yr and their baseline turnover marker, initial NTx values were significantly higher in those that gained bone than in those that lost bone (P = 0.0002). CS women in the highest quartile for NTx at baseline had significantly greater decreases in spine BMD than subjects with the lowest NTx values (P &lt; 0.005), although this was not true for fDpd (P &lt; 0.20). In conclusion, for early postmenopausal women there are differential responses of biochemical markers to HRT and CS. Baseline urinary NTx and serum OC were the most sensitive predictors of change in spine BMD after 1 yr of either HRT or CS. Similarly, the percent change in NTx and OC from baseline to 6 months best predicted bone gain or loss. We conclude that markers of bone formation and resorption can be used clinically to predict future BMD in early postmenopausal women.
Testing the Hypothalamic-Pituitary-Adrenal Axis in Survivors of Childhood Brain and Skull-Based Tumors1
Authors: Shankar R. Ravi , Jakacki Regina I. , Haider Anzar , Lee Melissa W. , Pescovitz Ora Hirsch 
Published: January 2014

Abstract
The objective of this study was to determine whether a low dose of ACTH (0.2 μg/kg) improves the sensitivity of ACTH testing in detecting hypothalamic-pituitary-adrenal (HPA) axis abnormalities in survivors of childhood brain and skull-based tumors.
Twenty-two children who had undergone treatment for brain or skull-based tumors were enrolled in a prospective study to extensively evaluate the HPA axis. Five tests of the adrenal axis were evaluated in each patient, including determination of basal serum cortisol, a standard ACTH test (250-μg iv bolus), a low dose ACTH test (0.2μ g/kg iv bolus), an insulin tolerance test, and a single dose metyrapone test.
Cortisol responses to both ACTH tests were nearly identical. Two patients (9%) failed the low dose ACTH test, whereas three (14%) failed the standard ACTH test; five of the children (23%) failed the insulin tolerance test, and five (23%) had abnormal responses to metyrapone. One child who initially passed the metyrapone test failed the test 19 months later after becoming symptomatic. All children with abnormal metyrapone test results had low levels of basal cortisol secretion.
In this study, the low dose ACTH test did not improve the sensitivity of ACTH testing for evaluation of the HPA axis. We conclude that a single morning basal cortisol level is a good screen for testing the HPA axis in children. We recommend confirming HPA axis dysfunction with the single dose metyrapone test, although this test also has limitations.
Differential Gene Expression of Steroid 5α-Reductase 2 in Core Needle Biopsies from Malignant and Benign Prostatic Tissue1
Authors: Bjelfman Catarina , Söderström Torbjörn G. , Brekkan Einar , Norlén Bo Johan , Egevad Lars , Unge Torsten , Andersson Stefan , Rane Anders 
Published: January 2014

Androgens are implicated in the development of prostate cancer (CAP) and benign prostate hyperplasia. The conversion of testosterone to the more potent metabolite dihydrotestosterone by prostate-specific steroid 5α-reductase type 2 (5α-red2) is a key mechanism in the action of androgens in the prostate and is important in the promotion and progression of prostate diseases. Manipulation of the turnover of androgens is thus fundamental in the pharmacological treatment strategy.
We have developed a sensitive solution hybridization method for quantification of the gene expression of 5α-red2 in core needle biopsies of the prostate. The 5α-red2-specific messenger RNA (mRNA) levels were measured in 50 human prostate transrectal ultrasound-guided core biopsies obtained from 31 outpatients (median age 72, range 57–88 yr) undergoing biopsy for diagnostic purposes. Significant differences were observed in the gene expression of 5α-red2 between cancerous and noncancerous tissue. In the 14 biopsies judged cancerous, the median 5α-red mRNA levels were 3.5 amol/ng total RNA compared with 12.0 amol/ng total RNA in the biopsies showing no cancer (P = 0.0018). The median 5α-red2 mRNA level in noncancerous tissue was thus 3.4 times higher than in the cancerous specimens.