bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Hormone-Sensitive Lipase Activity in Visceral and Subcutaneous Human Adipose Tissue1
Authors: Reynisdottir Signy , Dauzats Michèle , Thörne Anders , Langin Dominique
Published: January 2014

The possible role of hormone-sensitive lipase (HSL) in determining regional differences in lipolysis activation in humans was studied in vitro. Small adipose tissue biopsies were obtained from the abdominal sc and omental regions during surgery in 21 subjects spanning a wide range of body mass index (22–50 kg/m2). In lipolysis experiments, isolated fat cells were incubated with lipolytic agents acting at different levels in the lipolytic cascade. The activity and messenger ribonucleic acid expression of HSL were determined. The maximum lipolytic capacity was higher in sc than in omental fat cells as were HSL activity and messenger ribonucleic acid expression. The maximum lipolysis rate was significantly correlated to HSL activity. This is in accordance with the role of HSL as the rate-limiting step of lipolysis. However, adipocytes were 24% larger in the sc than in the omental region, and the lipolysis rate was significantly correlated to fat cell size regardless of either the region of origin or gender. This indicates that the regulation of HSL activity in healthy subjects, which appears to occur at a transcriptional level, is to a large extent dependent on fat cell size.
Thyrotropin Receptor Autoantibodies in Serum Are Present at Much Lower Levels Than Thyroid Peroxidase Autoantibodies: Analysis by Flow Cytometry*
Authors: Jaume Juan Carlos , Kakinuma Ayumu , Chazenbalk Gregorio D. , Rapoport Basil , McLachlan Sandra M.
Published: January 2014

Using Chinese hamster ovary (CHO) cells that express high numbers of TSH receptor (TSHR) on their surface, we studied the feasibility of detecting directly by flow cytometry the binding of autoantibodies in patients’ sera to the native TSHR. After using a serum (BBl) with high potency in the TSH binding inhibition (TBI) assay to establish the protocol, we studied an additional 38 sera: 10 without TBI activity (1–4.2% inhibition), 10 with moderately high TBI values (17.3–39.4% inhibition), 10 with high TBI levels (52–95.1% inhibition), 4 from normal individuals without autoimmune thyroid disease, and 4 from patients with systemic lupus erythematosus. We observed that a number of sera, including some without thyroid autoantibodies, contain antibodies against unknown antigens on CHO cells. Preadsorption with untransfected CHO cells before addition to the TSHR-10,000 cells eliminated or greatly reduced this nonspecific background. None of the sera from normal individuals, subjects with negative TBI values, or patients with systemic autoimmunity generated a positive signal on flow cytometry with TSHR-10,000 cells relative to the signal on untransfected cells. Remarkably, only 4 of 21 TBI-positive sera (including BBl) unequivocally recognized the TSHR on flow cytometry. In contrast, when thyroid peroxidase (TPO) autoantibodies in the same sera were studied using CHO cells overexpressing TPO on their surface, all 20 sera with TPO autoantibodies clearly elicited positive net fluorescence relative to untransfected cells. Study of the potent serum, BBl, revealed similar fluorescence (∼250 U) for TPO autoantibodies and TSHR autoantibodies at dilutions of 1:1000 and 1:10, respectively. Thus, by flow cytometry, the titer of TPO autoantibodies in the BBl serum is about 100-fold higher than that for TSHR autoantibodies in the same serum.

In conclusion, the present data provide the strongest support for the idea that TSHR autoantibodies in the sera of patients with autoimmune thyroid disease are present at much lower levels than are TPO autoantibodies. This finding has important implications for the diagnostic detection of TSHR autoantibodies and for understanding the pathogenesis of Graves’ disease.
The Differential Expression of Hepatocyte Growth Factor and Met in Human Placenta*
Authors: Kauma Scott , Hayes Natalie , Weatherford Shannon
Published: January 2014

Met is the tyrosine kinase receptor for the ligand hepatocyte growth factor (HGF). Met/HGF plays an important role in epithelial cell proliferation, migration, and morphogenesis. HGF also plays a crucial role in placental development in the mouse. To determine whether HGF potentially has a similar role in human placental development, the production and localization of Met and HGF were determined in early second trimester and term placentas. Reverse transcription-PCR using specific primers demonstrated the expression of Met and HGF messenger ribonucleic acid in placental villi. HGF production was determined by enzyme-linked immunosorbent assay. HGF production over 48 h by second trimester placental villous explants in culture (810 pg/mg total protein·h) was 2.1-fold greater than that in term placental villous explants (380 pg/mg total protein·h; P < 0.01). Isolated trophoblast did not produce HGF, whereas isolated villous core tissues and villous core mesenchymal cells did produce HGF. Interleukin-1β treatment of placental villi or coculture of villous core mesenchymal cells with isolated trophoblast cells did not stimulate HGF production. Using immunohistochemistry, HGF localized to the villous core compartment with no localization to the trophoblast. In contrast, Met localized mainly to cytotrophoblast. These findings suggest that HGF produced by the villous core may act in a paracrine fashion to regulate trophoblast development or function through the HGF receptor, Met.
Expression of Glucokinase in Glucose-Unresponsive Human Fetal Pancreatic Islet-Like Cell Clusters1
Authors: Tu Jian , Tuch Bernard E.
Published: January 2014

Glucokinase (GK) is the glucose sensor in the adult β-cell, resulting in fuel for insulin synthesis and secretion. Defects in this enzyme in the β-cell are responsible for the genetic disorder maturity-onset diabetes of the young, with the β-cell being unable to secrete insulin appropriately when challenged with glucose. The human fetalβ -cell is also unable to secrete insulin when exposed to glucose, but whether GK is present and functional in this developing cell is unknown. To determine the expression of GK in human fetal pancreatic tissue, cytosolic protein was extracted from human fetal islet-like cell clusters (ICCs) at 17–19 weeks gestation and examined for protein content and enzyme activity. On Western blots, a single band corresponding to GK was seen at 52 kDa, and this was similar to that obtained from human adult islets. The maximal velocity (Vmax) of GK was less in fetal ICCs than that in adult islets (8.7 vs. 20.7 nmol/mg protein·h); similar Km values were found in both ICCs and islets. No attempt was made to determine which cells in an ICC contained GK. Glucose utilization was determined radiometrically; the Vmax of the high Km component was less in ICCs than in islets (31.3 pmol/ICC·h vs. 101.4 pmol/islet·h). Culture of ICCs for 3–7 days in medium containing 11.2 mmol/L glucose resulted in a 3.7-fold increase in the Vmax of GK and a 1.8-fold increase in glucose utilization. These enhanced activities of glucose phosphorylation and glycolysis, however, did not lead to the β-cell being able to secrete insulin when exposed to glucose. In conclusion, glucokinase is present and functional in human fetal ICCs, but the inability of the human fetal β-cell to secrete insulin in response to an acute glucose challenge is not due to immaturity of this enzyme.
Detection of an Activating Mutation of the Thyrotropin Receptor in a Case of an Autonomously Hyperfunctioning Thyroid Insular Carcinoma1
Authors: Russo Diego , Tumino Salvatore , Arturi Franco , Vigneri Paolo , Grasso Giuseppe , Pontecorvi Alfredo , Filetti Sebastiano , Belfiore Antonino
Published: January 2014

Thyroid carcinomas, even when well differentiated, usually appear as hypofunctioning at scintigraphy. We report a case of an aggressive insular thyroid carcinoma presenting as an autonomously functioning thyroid nodule and causing severe thyrotoxicosis. The tumor was metastatic to a cervical lymph node and both lungs.

An activating mutation of the TSH receptor gene in both the primary tumor and the lymph node metastasis was found, due to a base substitution at codon 633 (normal guanine at position 1896 replaced by cytosine CAC for GAC causing aspartic acid substitution by histidine). Other known oncogenes (gsp, ras, PTC/ret, trk, met, and p53) were not involved.

This is the first description of an activating TSH receptor mutation in a thyroid hyperfunctioning carcinoma in which an aggressive malignant phenotype coexisted with activation of the cAMP cascade and differentiated thyroid functions.
Effects of Adrenomedullin on the Human Adrenal Glands: An in Vitro Study
Authors: Andreis P. G. , Neri G. , Prayer-Galetti T. , Rossi G. P. , Gottardo G. , Malendowicz L. K. , Nussdorfer G. G.
Published: January 2014

Numerous lines of evidence indicate that adrenal medulla exerts a paracrine control on the secretory activity of the cortex by releasing catecholamines and several regulatory peptides. Adrenomedullin (ADM) is contained in adrenal medulla of several mammalian species, including humans. Thus, we investigated whether human ADM1–52 exerts a modulatory action on steroid secretion of human adrenal cortex in vitro. Dispersed adrenocortical cells (obtained from the gland tail deprived of chromaffin cells) and adrenal slices (including both capsule and medulla) were employed. ADM specifically inhibited angiotensin II-stimulated aldosterone secretion of dispersed cells and enhanced basal aldosterone production by adrenal slices, minimal effective concentrations being 10−7 and 10−9 mol/L, respectively. These effects of ADM were suppressed by the CGRP1 receptor antagonist CGRP8–37 (10−5 mol/L). Neither basal and ACTH-stimulated aldosterone secretion of dispersed cells nor agonist-enhanced aldosterone production by adrenal slices were affected by ADM, which also did not alter cortisol secretion of both types of adrenal preparations. ADM (10−6 mol/L) blunted the aldosterone secretagogue action of the Ca2+ ionophore A23187 (10−5 mol/L) on dispersed cells and adrenal slices. Theβ -adrenoceptor antagonist l-alprenolol (10−6 mol/L) suppressed aldosterone response of adrenal slices to 10−7 mol/L isoprenaline and ADM. ADM concentration dependently raised epinephrine and norepinephrine release by adrenal slices, minimal effective concentration being 10−9 mol/L. Collectively, these findings suggest that ADM, acting via the CGRP1 receptor subtype, exerts a direct inhibitory effect on angiotensin II-stimulated aldosterone secretion, which, when the integrity of adrenal tissue is preserved, is overcome and reversed by an indirect stimulatory action, conceivably involving the release of catecholamines by adrenal chromaffin cells.
Increased Concentration of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Cyst Fluid of Enlarging and Recurrent Thyroid Nodules1
Authors: Sato Kanji , Miyakawa Megumi , Onoda Noritaka , Demura Hiroshi , Yamashita Tetsuji , Miura Masakazu , Kasajima Takeshi , Yamazaki Kazuko , Obara Takao
Published: January 2014

Human thyrocytes produce vascular endothelial growth factor (VEGF), a potent angiogenic factor, also known as vascular permeability factor (VPF), which increases vascular permeability. Based on the assumption that VEGF/VPF is involved in fluid accumulation in thyroid cysts, we determined the VEGF/VPF concentration in cyst fluids of thyroid nodules from 79 patients. VEGF/VPF was found to be abundantly present in the cyst fluids (0.02–183 ng/mL). There was no significant difference of VEGF/VPF concentration in the cyst fluid obtained from thyroid adenoma or from adenomotous goiter with cystic degeneration. Immunoreactive VEGF/VPF in cyst fluid was eluted mainly at 45 kDa, and stimulated endothelial cell proliferation, which was partially blocked by anti-VEGF/VPF antibody. The VEGF/VPF concentration in the cyst fluid obtained from patients who required repeated aspiration or underwent surgical resection because of recurrent accumulation (84.8 ± 58.3 ng/mL, mean ± sd, n = 18) was significantly higher than that in the cysts that regressed or disappeared after a single aspiration (4.3 ± 4.4 ng/mL, n = 12, P < 0.001).

These in vitro and clinical findings suggest that VEGF/VPF is at least partly involved in the accumulation of cyst fluid in thyroid nodules, and that a high VEGF/VPF concentration predicts rapid accumulation of the cyst fluid, possibly necessitating interventional treatment.
Increased 12-Lipoxygenase Expression in Breast Cancer Tissues and Cells. Regulation by Epidermal Growth Factor1
Authors: Natarajan Rama , Esworthy Robert , Bai Wei , Gu Jia-Li , Wilczynski Sharon , Nadler Jerry
Published: January 2014

The interaction of growth factors, such as epidermal growth factor (EGF) with their receptors, on breast cancer cells can lead to the hydrolysis of phospholipids and release of fatty acids, such as arachidonic acid, which can be further metabolized by the lipoxygenase (LO) pathway. Several LO products have been shown to stimulate oncogenes and have mitogenic and chemotactic effects. In this study, we have evaluated the regulation of 12-LO activity and expression in breast cancer cells and tissues. Leukocyte-type 12-LO messenger RNA (mRNA) expression was studied by a specific RT-PCR method in matched, normal, uninvolved and cancer-involved breast tissue RNA samples from six patients. In each of these six patients, the cancer-involved section showed a much higher level of 12-LO mRNA than the corresponding normal section. 12-LO mRNA levels also were greater in two breast cancer cell lines, MCF-7 and COH-BR1, compared with the nontumorigenic breast epithelial cell line, MCF-10F. The growth of the MCF-7 cells was significantly inhibited by two specific LO blockers but not by a cyclooxygenase blocker. Treatment of serum-starved MCF-7 cells with EGF for 4 h led to a dose-dependent increase in the formation of the 12-LO product, 12-hydroxyeicosatetraenoic acid. EGF treatment also increased the levels of the leukocyte-type 12-LO protein expression at 24 h. These results suggest that activation of the 12-LO pathway may play a key role in basal and EGF-induced breast cancer cell growth.
Serum α-Inhibin Levels in Polycystic Ovary Syndrome: Relationship to the Serum Androstenedione Level1
Authors: Pigny Pascal , Desailloud Rachel , Cortet-Rudelli Christine , Duhamel Alain , Deroubaix-Allard Delphine , Racadot André , Dewailly Didier
Published: January 2014

To date, only one study has demonstrated increased serum inhibin levels in women with polycystic ovary syndrome (PCOS). Moreover, no relationship between serum inhibin and either FSH or androgen levels has been noted. This lack of data could be due to 1) the heterogeneity of PCOS and the small sample size of previous studies, and/or 2) the complexity of circulating inhibin molecular forms, which hinders the precise evaluation of bioactive inhibin. In the present study,α -inhibin levels were assayed in the serum of 61 healthy women and 72 PCOS patients by means of an α-α enzyme-linked immunosorbent assay. Serum α-inhibin levels together with LH and androstenedione (A) levels were significantly increased in PCOS women (mean ± sd, 1.45 ± 0.55 vs. 0.94 ± 0.36 U/mL in controls; P < 0.001). Moreover, simple and partial regression analysis demonstrated that serum A levels were positively and independently correlated to serum α-inhibin (r = 0.32; P < 0.01) and LH levels (r = 0.48; P < 0.001) in PCOS. The respective influences of α-inhibin and LH on A variability were 20% and 80%, as determined by multiple regression analysis. In conclusion, in agreement with recent in vitro data, our in vivo results argue for a role of inhibin in the hyperandrogenism of PCOS together with, but independently from, that of LH. Further studies are needed to determine whether this effect is produced by inhibin A and/or B.
Allelic Loss in Parathyroid Tumors from Individuals Homozygous for Multiple Endocrine Neoplasia Type 11
Authors: Falchetti Alberto , Morelli Annamaria , Amorosi Andrea , Tonelli Francesco , Fabiani Silvia , Martineti Valentina , Castello Roberto , Furlani Lino , Brandi Maria Luisa
Published: January 2014

Homozygosity for the multiple endocrine neoplasia type 1 (MEN1) gene mutation was described in two of three affected siblings of a kindred in which both parents and the third daughter were heterozygotes. Surprisingly, in the two homozygotes, the disease history did not differ from the one of the heterozygotes. In the attempt to unravel genetic differences in parathyroid tumorigenesis between homozygotes and heterozygotes, restriction fragment length polymorphism analysis and microsatellite PCR analysis for loss of heterozygosity (LOH) at the MEN1 gene region on chromosome 11q13 was performed in parathyroid tissues removed at surgery from the mother, her heterozygous sister, and the three siblings. Allelic losses were evidenced in the larger glands of each patient, with a similar pattern of chromosome 11q12–13 losses. The somatic mutation consisted of a large loss of genetic material from chromosome 11. No gross differences exist in the 11q12–13 LOH observed between homozygous and heterozygous carriers. Interestingly, one of the parathyroid tumors from one heterozygote exhibited region of skipped LOH at the 11q12–13 region. The region in the depth of the critical interval retained heterozygosity, whereas those flanking it shared LOH. These findings indicate that inactivation of both copies of the MEN1 gene are not sufficient for parathyroid tumor development in MEN 1 patients and that tumor suppressor genes, other than the MEN1 gene on chromosome 11 or on other chromosomes, can be involved in the pathogenesis of parathyroid tumorigenesis in MEN 1 syndrome.
Fasting and Postprandial Lipid Abnormalities in Hypopituitary Women Receiving Conventional Replacement Therapy1
Authors: Al-Shoumer Kamal A. S. , Cox Katharine H. , Hughes Carol L. , Richmond William , Johnston Desmond G.
Published: January 2014

Hypopituitary patients, particularly women, have excess mortality, mostly due to vascular disease. We have studied circulating lipid and lipoprotein concentrations, fasting and over 24 h, in hypopituitary women and men and in matched controls. Firstly, 67 hypopituitary patients (36 women) and 87 normal controls (54 women) were studied after an overnight fast. Secondly, 12 patients (6 women) and 14 matched controls (7 women) were studied over 24 h of normal meals and activity. The patients were all GH deficient and were replaced with cortisol, T4, and sex hormones where appropriate, but not with GH. In the first study, circulating triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol were measured after an overnight fast. In the second study, fasting levels of apolipoprotein B, apolipoprotein A1, and lipoprotein(a) were also measured, and then circulating triglyceride and total cholesterol concentrations were measured over 24 h. Fasting concentrations of triglyceride (mean ± sem, 1.73 ± 0.22 vs. 1.11 ± 0.09 mmol/L; P = 0.0025), total cholesterol (6.45 ± 0.25 vs. 5.59± 0.21 mmol/L; P = 0.002), LDL cholesterol (4.58 ± 0.24 vs. 3.80 ± 0.19 mmol/L; P = 0.007), and apolipoprotein B (135 ± 10 vs. 111 ± 9 mg/dL; P = 0.048) were elevated in hypopituitary compared to control women. The lipid alterations were observed in older and younger women and occurred independently of sex hormone or glucocorticoid replacement. Fasting values were not significantly different in hypopituitary and control men. Patients and controls (women and men) had similar fasting HDL cholesterol, apolipoprotein A1, and lipoprotein(a) concentrations. Although the differences that existed in fasting lipid values were most marked in women, the men were also abnormal in this respect, in that a higher proportion of hypopituitary than control men had total and LDL cholesterol above recommended values (≥6.2 and ≥4.1 mmol/L, respectively). In the postprandial period (0730–2030 h), the areas under the curve (AUC) for circulating triglyceride and total cholesterol were significantly higher in hypopituitary than control women (P = 0.0089 and P = 0.0016, respectively). The AUC for triglyceride and total cholesterol over 24 h were also significantly increased (P= 0.009 and P = 0.0004, respectively). No significant differences were observed for postprandial and 24-h AUC for triglyceride and total cholesterol concentrations in men. We conclude that hypopituitarism with conventional replacement therapy is associated with unfavorable fasting and postprandial lipid and lipoprotein concentrations, particularly in women. The changes may contribute to the observed increased vascular morbidity and mortality.
Comparative Messenger Ribonucleic Acid Analysis of Immediate Early Genes and Sex Steroid Receptors in Human Leiomyoma and Healthy Myometrium
Authors: Lessl Monika , Klotzbuecher Michael , Schoen Silvia , Reles Angela , Stöckemann Klaus , Fuhrmann Ulrike
Published: January 2014

To shed light on the molecular mechanisms involved in the pathogenesis of uterine leiomyomas, transcript levels of the immediate early genes c-fos, c-myc, and c-jun and of the estrogen receptor (ER) and progesterone receptor (PR) were determined in tissue samples of human myometrium and leiomyoma. The messenger RNA (mRNA) content was analyzed by RT-PCR. mRNAs for c-fos, c-myc, c-jun, ER, and PR were detected in all 18 samples of leiomyoma and corresponding myometrial tissue collected in this study. Interestingly, in contrast to healthy tissues, we found a distinct and significant reduction of c-fos mRNA in the tumor. These data were substantiated by the finding of lowered c-Fos protein levels in leiomyomas tissues. Moreover, transcripts of c-jun and c-myc were less abundant in most of the leiomyomas than in the myometrium. This different expression of the protooncogenes in leiomyomas and myometrium was independent of the phase of the menstrual cycle in which samples were collected. In contrast to the reduced transcript levels observed for the immediate early genes, the ER and PR mRNA contents of the leiomyomas and myometrium did not differ. These results were confirmed by immunohistochemical studies for ER and PR protein.

In conclusion, our data show that the deregulated expression of protooncogenes, especially of c-fos, is linked to the pathogenesis of leiomyomas. Confirmation of a potential role of downregulated c-fos levels for the benign character of these tumors requires further investigation. Additionally, the findings suggest that sex steroids do not influence the different expression patterns of c-fos, c-myc, and c-jun in leiomyomas, as compared with myometrium.
Marked Decline in Serum Concentrations of Adrenal C19 Sex Steroid Precursors and Conjugated Androgen Metabolites During Aging
Authors: Labrie Fernand , Bélanger Alain , Cusan Lionel , Gomez José-Luis , Candas Bernard
Published: January 2014

The present data show a dramatic decline in the circulating levels of dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEA-S), androst-5-ene-3β,17β-diol (5-diol), 5-diol-sulfate, 5-diol-fatty acid esters, and androstenedione in both men and women between the ages of 20–80 yr. In the 50- to 60-yr-old group, serum DHEA decreased by 74% and 70% from its peak values in 20- to 30-yr-old men and women, respectively. The serum concentrations of the conjugated metabolites of dihydrotestosterone (DHT), namely androsterone (ADT)-G, androstane-3α,17β-diol (3α-diol-G), androstane-3β,17β-diol (3β-diol-G), and ADT-sulfate are the most reliable parameters of the total androgen pool in both men and women, whereas serum testosterone and DHT can be used as markers of testicular secretion in men and interstitial ovarian secretion in women. The serum concentration of these various conjugated androgen metabolites decreased by 40.8% to 72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in men and women, respectively, thus suggesting a parallel decrease in the total androgen pool with age. As estimated by measurement of the circulating levels of these conjugated metabolites of DHT, it is noteworthy that women produce approximately 66% of the total androgens found in men. In women, most of these androgens originate from the transformation of DHEA and DHEA-S into testosterone and DHT in peripheral intracrine tissues, whereas in men the testes and DHEA and DHEA-S provide approximately equal amounts of androgens at the age of 50–60 yr. An additional potentially highly significant observation is that the majority of the marked decline in circulating adrenal C19 steroids and their resulting androgen metabolites takes place between the age groups of 20- to 30-yr olds and 50- to 60-yr-olds, with smaller changes are observed after the age of 60 yr.
Methimazole and Propylthiouracil Equally Cross the Perfused Human Term Placental Lobule*
Authors: Mortimer R. H. , Cannell G. R. , Addison R. S. , Johnson L. P. , Roberts M. S. , Bernus I.
Published: January 2014

Propylthiouracil (PTU) is widely believed to cross the placenta less freely than methimazole (MMI) and is therefore regarded as the preferred drug for treatment of hyperthyroidism in pregnancy. Clinical studies comparing the two drugs show, however, no differences in maternal or fetal thyroid function. We investigated transfer from the maternal to the fetal circuit in the isolated perfused term human placental lobule of low and high doses of PTU (4 μg/mL and 40μ g/mL) and MMI (1.5 μg/mL and 15 μg/mL) in protein-free perfusate and low doses of both drugs with addition of 40 g/L of bovine albumin. Both drugs readily crossed the placenta, reaching equilibrium in all experiments in about 2 h. Drug concentrations in the two circuits fitted a two compartmental model. Transfer kinetics for the two drugs were similar, nonsaturable, and unaffected by addition of albumin. Clearances (mL·min−1·g−1, means ± sd) of PTU from maternal to fetal circuits were: 0.229± 0.110, 0.216 ± 0.065, and 0.170 ± 0.032; and for transfer of MMI: 0.165 ± 0.025, 0.232 ± 0.153, and 0.174 ± 0.009 (for low doses without, low doses with, and high doses without albumin, respectively). Clearances of PTU from fetal to maternal circuits were: 0.147 ± 0.072, 0.109 ± 0.014, and 0.116 ± 0.028; and for transfer of MMI: 0.095 ± 0.029, 0.122 ± 0.088, and 0.12 ± 0.005 (in the same experiments). There was no significant difference between drugs or drug doses and no effect of addition of albumin. We conclude that PTU and MMI have similar placental transfer kinetics.
Interleukin 1α Increases Serum Leptin Concentrations in Humans
Authors: Janik John E. , Curti Brendan D. , Considine Robert V. , Rager Helen C. , Powers Geraldine C. , Alvord W. Gregory , Smith John W. , Gause Barry L. , Kopp William C.
Published: January 2014

Leptin, the protein product of the ob gene, regulates appetite and body weight in animals. Endotoxin and cytokines, induced by endotoxin, interleukin (IL) 1 and tumor necrosis factor, increase expression of leptin in mice and hamsters. We measured serum leptin concentrations in patients with cancer before and after administration of recombinant human IL-1α. Fourteen patients received IL-1α at one of three dose levels (0.03, 0.1, or 0.3 μg/kg·day) for 5 days. Serum leptin concentrations increased in all but two patients within 24 h after the first dose. The increase in leptin was correlated directly with IL-1α dose (P = 0.0030). Despite continued administration of IL-1α, serum leptin concentrations returned to pretreatment levels by day 5 of therapy. An increase in serum leptin concentrations may be one mechanism by which anorexia is induced by IL-1α. However, tachyphylaxis of the leptin response suggests that other mechanisms also are involved.
Effect of Aging on the Sensitivity of Growth Hormone Secretion to Insulin-Like Growth Factor-I Negative Feedback*
Authors: Chapman Ian M. , Hartman Mark L. , Pezzoli Suzan S. , Harrell Frank E. , Hintz Raymond L. , Alberti K. G. M. M. , Thorner Michael O.
Published: January 2014

To determine the effect of aging on the suppression of GH secretion by insulin-like growth factor (IGF)-I, we studied 11 healthy young adults (6 men, 5 women, mean ± sd: 25.2 ± 4.6 yr old; body mass index 23.7 ± 1.8 kg/m2) and 11 older adults (6 men, 5 women, 69.5 ± 5.8 yr old; body mass index 24.2 ± 2.5 kg/m2). Saline (control) or recombinant human IGF-I (rhIGF-I) (2 h baseline then, in sequence, 2.5 h each of 1, 3, and 10 μg/kg·h) was infused iv during the last 9.5 h of a 40.5-h fast; serum glucose was clamped within 15% of baseline. Baseline serum GH concentrations (mean ± se: 3.3 ± 0.7 vs. 1.9 ± 0.5 μg/L, P = 0.02) and total IGF-I concentrations (219 ± 15 vs. 103 ± 19 μg/L, P < 0.01) were higher in the younger subjects. In both age groups, GH concentrations were significantly decreased by 3 and 10 μg/kg·h, but not by 1μ g/kg·h rhIGF-I. The absolute decrease in GH concentrations was greater in young than in older subjects during the 3 and 10 μg/kg·h rhIGF-I infusion periods, but both young and older subjects suppressed to a similar GH level during the last hour of the rhIGF-I infusion (0.78 ± 0.24 μg/L and 0.61 ± 0.16 μg/L, respectively). The older subjects had a greater increase above baseline in serum concentrations of both total (306 ± 24 vs. 244 ± 14 μg/L, P = 0.04) and free IGF-I (8.5 ± 1.4 vs. 4.2 ± 0.6 μg/L, P = 0.01) than the young subjects during rhIGF-I infusion, and their GH suppression expressed in relation to increases in both total and free serum IGF-I concentrations was significantly less than in the young subjects. We conclude that the ability of exogenous rhIGF-I to suppress serum GH concentrations declines with increasing age. This suggests that increased sensitivity to endogenous IGF-I negative feedback is not a cause of the decline in GH secretion that occurs with aging.
Phenotype and Genetic Analysis of a Syndrome Caused by an Inactivating Mutation in the Growth Hormone-Releasing Hormone Receptor: Dwarfism of Sindh1
Authors: Maheshwari Hiralal G. , Silverman Bernard L. , Dupuis Josée , Baumann Gerhard
Published: January 2014

We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 sd below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 sd, and blood pressure approximately 3 sd below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, l-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 ± 2.0 ng/mL and 0.42 ± 0.13 μg/mL, respectively; mean ± sd) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50→Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and l-dopa, but they showed only minimal or no height deficit.

This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.
Predictors of Short-Term Changes in Serum Intact Parathyroid Hormone Levels in Hemodialysis Patients: Role of Phosphorus, Calcium, and Gender1
Authors: Indridason Olafur S. , Pieper Carl F. , Quarles L. Darryl
Published: January 2014

Several factors have been identified as important in the pathogenesis of secondary hyperparathyroidism in end-stage renal disease, including serum calcium, phosphorus, and calcitriol. To examine the independent effects of key factors, we prospectively studied 52 new hemodialysis patients with mild secondary hyperparathyroidism (PTH, 110–670 pg/mL) treated with a standardized regimen of calcium supplements, phosphorus binders, and no vitamin D derivatives. We used simple and multivariable linear regression analysis to examine the relationship between changes in PTH (ΔPTH) levels observed over a 4-week period and various biochemical and demographic variables. By simple linear regression we found that changes in serum phosphorus (r2 = 0.31; β = 41.6; P = 0.0001), initial phosphorus concentration (r2 = 0.15; β = 33.4; P = 0.005), initial PTH level (r2 = 0.29; β = 0.58; P = 0.0001), changes in serum calcium (r2 = 0.12; β = −74.0; P = 0.01), and gender (r2 = 0.07; β = 76.1; P = 0.05) were significantly associated with ΔPTH. However, upon multivariable regression analysis, only the changes in phosphorus (partial r2 = 0.31; β = 37.0; P = 0.0001), initial PTH level (partial r2 = 0.23; β = 0.50; P = 0.0001), and gender (partial r2 = 0.05; β = 63.1; P = 0.02) remained significantly associated with ΔPTH. Neither the serum concentration of 1,25-dihydroxyvitamin D3, bicarbonate, aluminum, or albumin nor changes in the serum bicarbonate concentration, the presence of diabetes, KT/V, or age were significantly associated with theΔ PTH. Our findings are consistent with independent effects of phosphorus and gender on parathyroid gland function in patients with dialysis-dependent renal failure through mechanisms that remain to be defined.
Bone Mineral Recovery after Parathyroidectomy in Patients with Primary and Renal Hyperparathyroidism
Authors: Abdelhadi Mohamed , Nordenström Jörgen
Published: January 2014

Patients with hyperparathyroidism (HPT) generally display reduced bone mass due to excessive PTH activity. The effect of parathyroidectomy on bone mass changes in different types of HPT, however, is not well understood. Bone mineral density (BMD) was measured in the distal radius, total body, femoral neck, and lumbar spine by dual energy x-ray absorptiometry in four groups of patients with different hyperparathyroid conditions: primary symptomatic HPT (n = 54), primary asymptomatic (mild) HPT (n = 24), HPT associated with hemodialysis (n = 20), and HPT associated with renal transplant (n = 30). Subsets of patients with primary symptomatic HPT (n= 52), HPT associated with hemodialysis (n = 19), and HPT associated with renal transplant (n = 15) underwent parathyroidectomy, and bone density was measured longitudinally for 3 yr. Patients with primary asymptomatic (mild) HPT did not undergo surgery and were followed prospectively.

Before surgery, all groups showed a greater reduction of bone mineral density in cortical bone (distal radius) than in predominantly trabecular bone (lumbar spine). In primary symptomatic HPT, the BMD z-score of the distal radius was −1.80 ± 0.21 (±sem), and the corresponding figures for the total body, femoral neck, and lumbar spine were −0.60 ± 0.15, −0.54 ± 0.14, and −0.53 ± 0.18 compared with those of an age- and sex-matched reference group. In renal HPT BMD z-scores were −2.51± 0.38 (hemodialysis patients) and −2.83 ± 0.43 (renal transplant patients) for the distal radius and between −0.81 and− 1.46 for the other measured sites.

After parathyroidectomy, BMD increased by 1–8% at all sites in patients with primary symptomatic HPT and HPT associated with renal transplant. The largest increase in bone mass was observed in patients with HPT associated with hemodialysis, in whom the improvement amounted to 7–23%. In patients with primary HPT and HPT associated with hemodialysis, this increase in bone density resulted in virtual recovery from their preoperative bone loss. The majority of patients with asymptomatic primary HPT disease (n = 21) maintained their bone density during the follow-up period and have not shown evidence of increases in serum calcium or PTH levels, but three patients followed conservatively underwent parathyroidectomy due to progressive deterioration of BMD.

We conclude that, regardless of the etiology, a large proportion of HPT patients show reduced bone density. In patients with primary symptomatic HPT and patients with HPT associated with hemodialysis, bone density increases after parathyroidectomy to an extent that largely restores the preoperative bone loss. However, no anabolic effect of parathyroidectomy on bone mass was observed in patients with HPT associated with renal transplant, probably because of their immunosuppressive therapy.
Effect of Early Referral to an Endocrinologist on Efficiency and Cost of Evaluation and Development of Treatment Plan in Patients with Thyroid Nodules
Authors: Ortiz Robert , Hupart Kenneth H. , DeFesi Charles R. , Surks Martin I.
Published: January 2014

Radionuclide uptake and scan and sonogram, frequently ordered before referral to an endocrinologist, are expensive and poor predictors of thyroid nodule malignancy. We estimated costs of excessive imaging and other studies by reviewing the records of all patients (n = 70) referred to a single, consulting endocrinologist, for thyroid nodule evaluation in a 2-yr interval and subsequently, presenting only pertinent histories and results of physical examinations, thyroid function tests, and thyroid autoantibodies, to a second, reviewing endocrinologist (RE) who was blinded to diagnosis and management. Concordance in diagnosis and management between consulting endocrinologist and RE was 87.1% and 93.4%, respectively. Accuracy of diagnosis, loss of patient’s time (8.7 h, average), and cost of unnecessary testing, defined as tests not required by the RE for diagnosis and management according to published guidelines, were determined. Unnecessary testing included 153 physician’s office or diagnostic laboratory visits, 44 sets of thyroid function tests, 32 radionuclide uptake and scan, 39 thyroid sonograms, and 3 computed tomography scans. The total direct cost of unnecessary tests was estimated at $27,290 ($390/patient) in addition to costs of 30 unnecessary physician’s office visits. Only 2 of 8 surgical referrals required surgery, whereas 6 other patients required surgery, including 3 with papillary carcinoma. We conclude that early referral to an endocrinologist of patients with suspected thyroid nodules results in significant savings in cost of evaluation, patient’s time, and increased diagnostic precision. Six of the 8 patients referred for surgery before endocrine consultation had benign thyroid disease that did not require surgery. Six additional patients were referred to surgery, 3 of whom had papillary thyroid carcinoma.

Early referral of patients with suspected thyroid nodules to an endocrinologist results in significant savings in both cost and patient’s time as well as increased precision of diagnosis.
Relation among Left Ventricular Mass, Insulin Resistance, and Blood Pressure in Nonobese Subjects1
Authors: Phillips Robert A. , Krakoff Lawrence R. , Dunaif Andrea , Finegood Diane T. , Gorlin Richard , Shimabukuro Seiichi
Published: January 2014

Because left ventricular (LV) mass (LVM) is a powerful predictor of future cardiovascular events, it is important to identify hemodynamic and nonhemodynamic factors that increase LVM. We studied the separate contribution to LVM of daily arterial blood pressure (BP) and insulin resistance in a consecutive series of 29 (mean ± sd age, 43 ± 13 yr) nonobese (body mass index, 24 ± 1.8 kg/m2), nondiabetic, glucose-tolerant subjects with untreated borderline or mild hypertension. The insulin sensitivity index (SI) was quantitatively determined from the frequently sampled iv glucose tolerance test. BP was characterized by ambulatory 24-h BP monitoring, and LVM index (LVMI) was determined by two-dimensional directed M-mode echocardiography. LVMI was directly related to 24-h mean BP (r = 0.47; P = 0.01). LMVI was also significantly related to SI (r = −0.43; P = 0.02). In this nonobese group, neither LVMI nor SI was related to body mass index or age. After adjustment for the influence of BP on LVMI, a significant relation remained between LVMI and SI (P < 0.05).

We conclude that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP and may be an important modulator of LV growth. In addition to a reduction of arterial BP, optimal prevention of LV hypertrophy in hypertensives may require improved insulin sensitivity.
Determinants of Serum Leptin Levels in Cushing’s Syndrome
Authors: Widjaja Adji , Schürmeyer Thomas H. , Von Zur Mühlen Alexander , Brabant Georg
Published: January 2014

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing’s syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 ± 2.7 yr; body mass index (BMI), 29.6 ± 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 ± 3.1 yr; BMI, 26.3 ± 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing’s syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing’s syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.
Imaging of the Buffering Effect of Insulin Antibodies in the Autoimmune Hypoglycemic Syndrome1
Authors: Dozio Nicoletta , Scavini Marina , Beretta Angelo , Sarugeri Elena , Sartori Stefano , Belloni Cristina , Dosio Flaviano , Savi Annarita , Fazio Ferruccio , Sodoyez Jean Claude , Pozza Guido
Published: January 2014

Insulin autoimmune hypoglycemia is characterized by recurrent hypoglycemia and high levels of immunoreactive insulin in the presence of insulin autoantibodies. The mechanisms inducing hypoglycemia are largely unknown. An [123I]insulin scintigraphic scanning was performed to directly demonstrate the effect of antibodies on insulin biodistribution in one patient with this syndrome both before and after treatment. The patient had insulin autoantibodies IgG3 λ, which had a single site dissociation constant (Kd = 10−7 mol/L, by Scatchard analysis), a very fast dissociation rate of immune complexes, and a very rapid association of[ 125I]insulin. Insulin receptors on red blood cells were down-regulated. The [123I]insulin scintigraphic study imaged the buffering effect of antibodies on insulin bioavailability.[ 123I]Insulin was not removed from the blood, and no liver or kidney uptake of the hormone occurred. The frequency and severity of hypoglycemic episodes required treatment. Insulin antibody levels decreased and [123I]insulin biodistribution improved after treatment with plasmapheresis and prednisone. Improved hormone bioavailability was further evidenced by the reduction in the hypoglycemic delay after iv insulin from 90 min before any treatment to 60 min after plasmapheresis and 30 min after steroid administration. Glucose tolerance was normal after treatment. Plasmapheresis followed by steroid treatment can lower the insulin antibody concentration, abolish severe hypoglycemia, and improve insulin biodistribution and glucose tolerance in insulin autoimmune hypoglycemia.
Elevated Plasma Cortisol Concentrations: A Link between Low Birth Weight and the Insulin Resistance Syndrome?1
Authors: Phillips D. I. W. , Barker D. J. P. , Fall C. H. D. , Seckl J. R. , Whorwood C. B. , Wood P. J. , Walker B. R.
Published: January 2014

Recent studies have shown that reduced fetal growth is associated with the development of the insulin resistance syndrome in adult life. The mechanisms are not known. However increased activity of the hypothalamic-pituitary-adrenal axis (HPAA) may underlie this association; the axis is known to be reset by fetal growth retardation in animals, and there is evidence in humans of an association between raised HPAA activity and the insulin resistance syndrome. We have, therefore, examined the relations among size at birth, plasma cortisol concentrations, and components of the insulin resistance syndrome in a sample of healthy men. We measured 0900 h fasting plasma cortisol and corticosteroid-binding globulin levels in 370 men who were born in Hertfordshire, UK, between 1920–1930 and whose birth weights were recorded. Fasting plasma cortisol concentrations varied from 112–702 nmol/L and were related to systolic blood pressure (P = 0.02), fasting and 2-h plasma glucose concentrations after an oral glucose tolerance test (P = 0.0002 and P = 0.04), plasma triglyceride levels (P = 0.009), and insulin resistance (P = 0.006). Plasma cortisol concentrations fell progressively (P = 0.007) from 408 nmol/L in men whose birth weights were 5.5 lb (2.50 kg) or less to 309 nmol/L among those who weighed 9.5 lb (4.31 kg) or more at birth, a trend independent of age and body mass index. These findings suggest that plasma concentrations of cortisol within the normal range could have an important effect on blood pressure and glucose tolerance. Moreover, this study provides the first evidence that intrauterine programming of the HPAA may be a mechanism underlying the association between low birth weight and the insulin resistance syndrome in adult life.