bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of the Baboon Fetal Adrenal Gland: Regulation of the Ontogenesis of the Definitive and Transitional Zones by Adrenocorticotropin*
Authors: Leavitt Maria G. , Albrecht Eugene D. , Pepe Gerald J. 
Published: January 2014

Abstract
Throughout gestation, the primate fetal adrenal gland is comprised of the fetal zone, which expresses the P-450 17α-hydroxylase-C17,20 lyase (P-450c17) enzyme that catalyzes the synthesis of C19 steroids used for placental estrogen production. The development of the transitional zone comprised of cortical cells that express the P-450c17 and the 3β-hydroxysteroid dehydrogenase-isomerase (3βHSD) enzymes for cortisol production, and the definitive zone, which expresses 3βHSD, but not P-450c17, for mineralocorticoid synthesis, does not occur until relatively late in gestation. Although ACTH is considered essential to fetal adrenal growth and function, the role that ACTH has in the development of the transitional and definitive zones, is less clear. To answer this question, the width of these zones was determined by immunocytochemical expression of P-450c17 and/or 3βHSD in fetal adrenal glands obtained on day 100 (mid) of gestation (term = day 184) from baboons in which ACTH was administered to the fetus on days 95–99 of gestation or on day 165 (late) of gestation from baboons in which fetal ACTH was suppressed by treatment of the mother and fetus with betamethasone on days 150–164 of gestation. At midgestation, the fetal adrenal was comprised almost exclusively of fetal zone cells and a small definitive zone (38 ± 2 μm in width), but was essentially devoid of a transitional zone (7 ± 2 μm). Treatment with ACTH enhanced (P &lt; 0.05) the width of the transitional zone (67 ± 4 μm), but not the size of the definitive zone (10 ± 4 μm). In late gestation, the width of the definitive zone, although 2-fold greater than that on day 100, was smaller (P &lt; 0.05) than that of the transitional zone (120 ± 15 μm), which greatly exceeded that at midgestation. Treatment with betamethasone in late gestation eliminated the transitional zone, but had no effect on the size of the definitive zone (120 ± 8 μm). These findings indicate that the development of the baboon fetal adrenal transitional zone late in gestation is dependent on fetal pituitary ACTH. In contrast, the ontogenesis of the definitive zone at midgestation and its growth in late gestation occur in the relative absence of ACTH.
Relationship Between Insulin Resistance, Soluble Adhesion Molecules, and Mononuclear Cell Binding in Healthy Volunteers*
Authors: Chen Neng-Guin , Holmes Margot , Reaven Gerald M. 
Published: January 2014

Abstract
The relationship between insulin resistance, soluble adhesion molecules E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1), and vascular adhesion molecule-1 (sVCAM-1), mononuclear cell binding to cultured endothelium, and lipoprotein concentrations were evaluated in 28 healthy, nondiabetic, and normotensive individuals. The mean (±sem) lipid and lipoprotein concentrations were within the normal rage: cholesterol (199 ± 18 mg/dL); triglyceride (128 ± 12 mg/dL); low-density cholesterol (127 ± 8 mg/dL; and high-density cholesterol (47 ± 3 mg/dL). The results indicated that degree of insulin resistance was significantly correlated with concentrations of sE-selectin (r = 0.54, P &lt; 0.005), sICAM-1 (r = 0.67, P &lt; 0.001), and sVCAM-1 (r = 0.41, P &lt; 0.05). Furthermore, the relationship between insulin resistance and both sE-selectin and sICAM-1 remained statistically significant when adjusted for differences in age, gender, body mass index, and all measures of lipoprotein concentrations. Finally, mononuclear cell binding correlated significantly with concentrations of sE-selectin (r = 0.54, P &lt; 0.005) and sICAM-1 (r = 0.47, P &lt; 0.01). These findings raise the possibility that previously described relationships between soluble adhesion molecules in patients with hypertension, type 2 diabetes, and dyslipidemia may be due to the presence of insulin resistance in these clinical syndromes and suggests that insulin resistance may predispose individuals to coronary heart disease by activation of cellular adhesion molecules.
Independent Regulation of Matrix Metalloproteinase-9, Tissue Inhibitor of Metalloproteinase-1 (TIMP-1), and TIMP-3 in Human Endometrial Stromal Cells by Gonadotropin-Releasing Hormone: Implications in Early Human Implantation1
Authors: Raga Francisco , Casañ Eva Maria , Wen Yan , Huang Hong-Yuan , Bonilla-Musoles Fernando , Polan Mary Lake 
Published: January 2014

Early human trophoblast shows dramatic invasive properties during early pregnancy. The simultaneous synthesis of matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs) in both human trophoblast and decidual membranes suggests that their controlled and balanced expression is crucial for the rapid matrix remodeling and controlled invasion during early pregnancy.Recently, we have described the presence of an extrahypothalamic GnRH immunologically, biologically and chemically identical to the hypothalamic hormone in periimplantation human embryos. Moreover, the production of this decapeptide by the human trophoblast during the early stages of placentation is well documented.TIMP-1 and -3 messenger ribonucleic acid (mRNA) expression in cultured stromal cells and protein secretion into the medium were significantly decreased by GnRH agonist compared to that in control groups. Moreover, expression of TIMP-1 was affected to a greater extent than that of TIMP-3. GnRH antagonist ablated the down-regulation of TIMPs by the GnRH agonist. MMP-9 mRNA expression was not detected in the control groups or in the groups treated with GnRH analogs.Our results provide evidence that trophoblastic GnRH may play an important role in placental tissue organization and in the early embryo-maternal dialogue by enhancing trophoblast invasion through the specific inhibition of TIMPs.
The Effects of Dose, Nutrition, and Age on Hexarelin-Induced Anterior Pituitary Hormone Secretion in Adult Patients on Maintenance Hemodialysis1
Authors: Jenkins Richard C. , Meguid El Nahas A. , Wilkie Martin E. , Brown Colin B. , Jones Jenny , Ghigo Ezio , Ross Richard J. M. 
Published: January 2014

Malnutrition is common in chronic renal failure (CRF) and adversely affects prognosis. In view of the anabolic action of GH in CRF, we have studied the effects of hexarelin, a GH secretagogue, on CRF. An iv dose-response study in six 20- to 40-yr-old well nourished hemodialysis (HD) patients was followed by administration of the maximally effective dose to six 20- to 40-yr-old healthy controls, six 20- to 40-yr-old poorly nourished HD patients, and six 50- to 70-yr-old poorly nourished HD patients.
GH secretion (area under the curve over 180 min, mean ± se) after 2 and 1 μg/kg doses (10.7 ± 4.2 and 8.2 ± 5.2 min/U·L, respectively) was greater than after placebo (0.60 ± 0.11 min/U·L; P &lt; 0.001 and P &lt; 0.05, respectively). The most effective dose (2 μg/kg) produced similar GH secretion (11.4 ± 3.3 min/U·L) in controls. GH secretion in the younger poorly nourished HD group (19.0 ± 4.4 min/U·L) was not significantly different from that in the well nourished 20- to 40-yr-old HD patients (P = 0.06). GH secretion in the older, poorly nourished HD patients (9.4 ± 2.2 min/U·L) was similar to that in the young, poorly nourished group (P = 0.18). ACTH and cortisol concentrations increased in all groups, whereas PRL concentrations were not affected in CRF.
The profound action of hexarelin on GH secretion has been shown to extend to CRF. Trends were evident toward increasing efficacy in malnourished subjects and decreasing efficacy with age. Further studies are required to determine whether the acute actions of hexarelin can be translated into long term anabolic changes.
Estrogen Activity and Novel Tissue Selectivity ofΔ 8,9-Dehydroestrone Sulfate in Postmenopausal Women
Authors: Baracat E. , Haidar M. , López F. J. , Pickar J. , Dey M. , Negro-Vilar A. 
Published: January 2014

Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells.Δ 8,9-Dehydroestrone sulfate (Δ8,9-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17β form, 17β-Δ8,9-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with Δ8,9-DHES and estrone sulfate as a comparator in postmenopausal women. Δ8,9-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of Δ8,9-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with Δ8,9-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker, i.e. urinary excretion of N-telopeptide, demonstrated that Δ8,9-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving Δ8,9-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after Δ8,9-DHES administration.
Taken together with preclinical data, it is found thatΔ 8,9-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens. Collectively, this information supports the concept thatΔ 8,9-DHES is an integral component of CEE, with distinct tissue selectivity contributing to the CEE’s overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.
Lactate and Glycerol Release from Subcutaneous Adipose Tissue in Black and White Lean Men1
Authors: van der Merwe Maria-Terésa , Jansson Per-Anders , Crowther Nigel J. , Boyd Ivan H. , Gray I. Peter , Joffe Barry I. , Lönnroth Peter N. 
Published: January 2014

To measure interstitial glycerol and lactate production from the sc adipose tissue of two regions in nine black and nine white lean men, sc microdialysis was performed in combination with adipose tissue blood flow rates measured with 133Xe clearance.
In the postabsorptive state, the plasma glucose and insulin levels of the black men and white men were similar. The black men had higher plasma free fatty acids (825 ± 97 vs. 439 ± 58 μmol/L; P &lt; 0.005), glycerol (99.5 ± 5.1 vs. 54.1 ± 3.3 μmol/L; P&lt; 0.0001), and lactate (1056 ± 95 vs. 729 ± 45 μmol/L; P &lt; 0.01). Interstitial glycerol concentrations in the black and white men were 227 vs. 163 μmol/L (P &lt; 0.01) and 230 vs. 162 μmol/L (P &lt; 0.05) in the abdominal and femoral regions. The adipose tissue blood flow rate was higher in the black men in the abdominal (7.9 ± 0.9 vs. 3.1± 0.5 mL/100 g·min; P &lt; 0.01) and femoral area (5.2 ± 0.6 vs. 2.8 ± 0.3; P &lt; 0.01). Interstitial lactate concentrations in black and white men were 1976 vs. 1364 μmol/L (P &lt; 0.004) and 1953 vs. 1321μ mol/L (P &lt; 0.004) in the abdominal and femoral regions, respectively. Glycerol release was higher in black men vs. white men for abdominal (0.21 ± 0.02 vs. 0.14 ± 0.02 μmol/100 g·min; P &lt; 0.02) and femoral (0.22 ± 0.02 vs. 0.15 ± 0.01; P &lt; 0.05) areas.
Postprandially, black men had higher plasma glucose levels [1 h, 9.6 ± 0.4 vs. 8.2 ± 0.5 mmol/L (P &lt; 0.05); 2 h, 8.9 ± 0.4 vs. 7.2 ± 0.4 mmol/L (P &lt; 0.01)], but lower plasma insulin levels [1 h, 173 ± 13 vs. 264 ± 48 pmol/L (P &lt; 0.05); 2 h, 136 ± 20 vs. 209 ± 34 pmol/L (P &lt; 0.05)]. Plasma free fatty acid, lactate, and glycerol levels remained higher in the black men. After 1 h, lactate release was higher in the black men vs. that in the white men for abdominal (20.5 ± 1.6 vs. 14.7 ± 2.5 μmol/100 g·min; P &lt; 0.05) and femoral (15.6 ± 1.1 vs. 12.1 ± 1.8; P &lt; 0.03) areas.
We conclude that the black men, who are relatively insulinopenic postprandially, have a brisker lipolysis and also release more lactate from sc fat tissue than white men. These differences in adipose tissue metabolism may be related to differences in the lipid profiles and glucose metabolism previously documented in these ethnic groups.
Estrogen Priming Effect on Growth Hormone (GH) Provocative Test: A Useful Tool for the Diagnosis of GH Deficiency1
Authors: MartÍnez Alicia S. , Domené Horacio M. , Ropelato M. Gabriela , Jasper Héctor G. , Pennisi Patricia A. , Escobar MarÍa E. , Heinrich Juan J. 
Published: January 2014

We have studied the effect of estradiol (E2)on the GH-insulin-like growth factor (GH-IGF) axis in 15 prepubertal GH deficiency (GHD) children and 44 prepubertal or early pubertal children with idiopathic short stature (SS). All of them received a daily dose of micronized E2 (1 or 2 mg) or placebo, for 3 days, before a sequential arginine-clonidine test. In SS children, GH maximal responses were 17.8 ± 10.9 on placebo and 27.9 ± 14.5μ g/L on estrogen (P &lt; 0.0001). The lower 95% confidence limits for GH maximal response changed from 3.7 μg/L (without E2) to 8.3 μg/L (on E2). In GHD children, no significant stimulatory effect of estrogen on GH levels was observed. After placebo, a cut-off limit of 3.7 μg/L (the lower 95% confidence interval limit) resulted in 73% sensitivity, 95% specificity, and an overall 90% diagnostic efficiency. After E2, a cut-off limit of 8.3 μg/L resulted in a sensitivity of 87%, a specificity of 98%, and a diagnostic efficiency of 95%.After placebo, 68% of SS showed normal IGF-I levels, and the mean did not change on E2 (13.7 ± 6.3 vs. 14.3 ± 6.8 nmol/L, not significant). In 93% of SS, IGF binding protein (IGFBP)-3 levels were normal during placebo. On E2, mean IGFBP-3 did not change (2.63 ± 0.70 vs. 2.70 ± 0.70 mg/L, not significant). In 14 of 15 GHD patients, IGF-I values were below normal on placebo, and the mean of the group did not change after E2. During placebo, 13 of 15 GHD children presented low IGFBP-3 values. During E2, there was a small significant increase in IGFBP-3 values (1.06 ± 0.58 vs. 1.20 ± 0.69 mg/L, P &lt; 0.02). The highest diagnostic efficiencies for IGF-I and IGFBP-3 were observed during placebo (75% and 91%, respectively).We conclude that GH stimulation tests after E2 priming had the highest diagnostic efficiency. Our findings suggest that the effect of estrogen priming on GH stimulated levels, by reducing the number of false nonresponders, might be useful to better discriminate between normal and abnormal GH status in SS children.
The Localization of the Functional Glucocorticoid Receptor α in Human Bone
Authors: Abu Emmanuel O. , Horner A. , Kusec V. , Triffitt J. T. , Compston J. E. 
Published: January 2014

Glucocorticoids have well-documented effects on the skeleton, although their mechanism of action is still poorly understood. The actions of glucocorticoids on bone cells are mediated, in part, directly via specific receptors. The presence of these receptors has been demonstrated in both rodent and human osteoblastic cells in vitro, but their presence in human bone in vivo has not been reported.
In this study, we have used specific affinity purified polyclonal antibodies to the functional glucocorticoid receptor α (GRα) to investigate its expression in both developing and adult human bone using sections of neonatal rib, calvarial, and vertebral bones, tibial growth plates from adolescents, and iliac crest biopsies from adults who were to undergo liver transplantation.
In the tibial growth plates, GRα was predominantly expressed in the hypertrophic chondrocytes within the cartilage. In the primary spongiosa, the receptor was highly expressed by osteoblasts at sites of bone modeling. Within the bone marrow, receptors were also detected in mononuclear cells and in endothelial cells of blood vessels. In the neonatal rib and vertebrae, GRα was widely distributed at sites of endochondral bone formation in resting, proliferating, mature, and hypertrophic chondrocytes. They were also highly expressed in osteoblasts at sites of bone modeling. At sites of intramembranous ossification in neonatal calvarial bone and rib periosteum, GRα was widely expressed in cells within the fibrous tissue and in osteoblasts at both the bone-forming surface and at modeling sites. In the iliac crests from adults, GRα was predominantly expressed in osteocytes. The receptors were not detected in osteoclasts.
Our results show for the first time the presence of the functional GRα in human bone in situ and suggest that the actions of glucocorticoids on bone may be mediated, in part, directly via the GR at different stages of life. The absence of receptor expression in osteoclasts also suggests that the effects of glucocorticoids on bone resorption may be mediated indirectly.
No Increased Insulin Sensitivity after a Single Intravenous Administration of a Recombinant Human Tumor Necrosis Factor Receptor: Fc Fusion Protein in Obese Insulin-Resistant Patients*
Authors: Paquot Nicolas , Castillo Manuel J. , Lefèbvre Pierre J. , Scheen Andre J. 
Published: January 2014

AbstractInhibition of tumor necrosis factor (TNF)-α results in a marked increase in insulin sensitivity in obese rodents. We investigated the influence of a TNF antagonist [Ro 45-2081, a recombinant fusion protein that consists of the soluble TNF-receptor (p55) linked to the Fc portion of human IgG1] on insulin sensitivity of patients with android obesity. Seven patients (five women and two men; mean ± sd age, 41 ± 4 yr; body mass index, 36.1 ± 4.7 kg/m2; waist to hip ratio, 0.99 ± 0.11) were studied (three patients with normal glucose tolerance and four patients with impaired glucose tolerance or mild diabetes; all were hyperinsulinemic). Each patient underwent two consecutive euglycemic hyperinsulinemic glucose-clamp tests: 48 h after injection of placebo and 48 h after a single iv injection of 50 mg Ro 45-2081. In both tests, steady-state plasma glucose and insulin levels were similar. Insulin-mediated glucose disposal (2.23 ± 0.74 vs. 2.38 ± 0.99 mg/kg−1·min−1) and glucose metabolic clearance rate (2.28 ± 0.85 vs. 2.48 ± 1.03 mL/kg−1·min−1) were similar after placebo and after the drug. Indirect calorimetry showed no difference in substrate oxidation rates between the two experimental conditions. In conclusion, under the conditions of this study, no improvement in insulin sensitivity was observed in obese insulin-resistant patients following a single iv administration of a recombinant TNF receptor: Fc fusion protein.
Respiratory Fitness, Free Living Physical Activity, and Cardiovascular Disease Risk in Older Individuals: A Doubly Labeled Water Study*
Authors: Dvorak Roman V. , Tchernof André , Starling Raymond D. , Ades Philip A. , DiPietro Loretta , Poehlman Eric T. 
Published: January 2014

Abstract
The objective of this study was to examine the importance of cardiorespiratory fitness vs. physical activity energy expenditure on selected cardiovascular disease risk factors in older individuals. One hundred and seventeen older individuals, 53 men (68 ± 9 yr) and 63 women (67 ± 7 yr), participated in the study. This cohort was divided into 4 groups: 1) high cardiorespiratory fitness and high physical activity, 2) high cardiorespiratory fitness and low physical activity, 3) low cardiorespiratory fitness and high physical activity, and 4) low cardiorespiratory fitness and low physical activity. Cardiorespiratory fitness (VO2max) was determined from a graded exercise test, physical activity energy expenditure was measured by doubly labeled water and indirect calorimetry, body composition was determined by dual energy x-ray absorptiometry, and dietary practices were determined by a 3-day recall. Cardiorespiratory fitness exerted greater effects on the cardiovascular disease risk profile than physical activity. That is, older individuals with higher levels of cardiorespiratory fitness, regardless of their physical activity levels, showed lower levels of fasting insulin (P &lt; 0.01), triglycerides (P &lt; 0.05), total cholesterol (P &lt; 0.05), total to high density lipoprotein cholesterol ratio (P &lt; 0.05), low density lipoprotein (P &lt; 0.05), and lower waist circumference (P &lt; 0.01). Moreover, individuals with a high cardiorespiratory fitness but low physical activity energy expenditure displayed a more favorable cardiovascular disease risk profile than individuals with low cardiorespiratory fitness and high physical activity energy expenditure. The results suggest that higher levels of cardiorespiratory fitness have greater cardioprotective effects than higher levels of free living physical activity in older individuals. Although these findings do not discount the health benefits of being physically active, it is possible that greater emphasis should be placed on aerobic exercise to increase cardiorespiratory fitness in the elderly.
Effect of Vitamin D Nutrition on Parathyroid Adenoma Weight: Pathogenetic and Clinical Implications*
Authors: Rao D. Sudhaker , Honasoge M. , Divine George W. , Phillips Evelyn R. , Lee Min W. , Ansari Mohammed R. , Talpos Gary B. , Parfitt A. Michael 
Published: January 2014

Abstract
In primary hyperparathyroidism, adenoma size is a major determinant of disease severity and manner of presentation, but the reason for the large variation in size (&gt;100-fold) is unknown. One factor could be the level of vitamin D nutrition, because in India, where vitamin D deficiency is endemic, adenomas are larger and the disease more severe than in the U.S. Accordingly, we determined the relationship between vitamin D nutrition, as measured by serum levels of 25-hydroxyvitamin D (25OHD), and parathyroid gland weight, expressed on a logarithmic scale, in 148 U.S. patients with primary hyperparathyroidism.
A significant inverse relationship was found between log gland weight as dependent variable and serum 25OHD as independent variable (r =− 0.365; P &lt; 0.0001). The only other influence on gland weight was a weak inverse correlation with age. Log gland weight as an independent variable was significantly related to adjusted calcium, PTH, and alkaline phosphatase (AP) as dependent variables. In 51 patients with serum 25OHD levels less than 15 ng/mL, gland weight, PTH, AP, and adjusted calcium were each significantly higher than in 97 patients with 25OHD levels of 15 ng/mL or more, but 1,25-dihydroxyvitamin D levels were similarly increased in both groups. In the former group the response of adjusted calcium to PTH was blunted, and the response of AP was enhanced, based on significant differences in regression slopes (P = 0.0004 and 0.0022, respectively).
Suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to hypocalcemia or 1,25-dihydroxyvitamin D deficiency and reduces the calcemic response to PTH, so that a higher PTH level and more parathyroid cells are needed to raise the patient’s serum calcium to the level corresponding to the increased set-point that is characteristic of the disease. Improved vitamin D nutrition in the population is partly, perhaps largely, responsible for the historical changes in disease severity and manner of presentation that have occurred over the last 50 yr.