bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Mutation in the LHX3 Gene is Responsible for Combined Pituitary Hormone Deficiency, Hearing Impairment, and Vertebral Malformations
Authors: Kriström Berit , Zdunek Anna-Maija , Rydh Anders , Jonsson Håkan , Sehlin Petra , Escher Stefan A. 
Published: January 2014

Abstract
Context: The LHX3 LIM-homeodomain transcription factor gene, found in both man and mouse, is required for development of the pituitary and motor neurons and is also expressed in the auditory system.
Objective: The objective of this study was to determine the cause of, and further explore, the phenotype in six patients (aged 6 months to 22 years) with combined pituitary hormone deficiency (CPHD), restricted neck rotation, scoliosis and congenital hearing impairment. Three of the patients also have mild autistic-like behaviour.
Design: As patients with CPHD and restricted neck rotation have previously been shown to have mutations in the LHX3 gene, a candidate gene approach was applied and the gene was sequenced. Neck anatomy was explored by computed tomography and magnetic resonance imaging, including three-dimensional reformatting.
Results: A novel, recessive, splice-acceptor site mutation was found. The predicted protein encoded by the mutated gene lacks the homeodomain and carboxyl terminus of the normal, functional protein. Genealogical studies revealed a common gene source for all six families dating back to the seventeenth century. Anatomical abnormalities in the occipito–atlanto–axial joints in combination with a basilar impression of the dens axis were found in all patients assessed.
Conclusions: This study extends both the mutations known to be responsible for LHX3-associated syndromes and their possible phenotypic consequences. Previously reported traits include CPHD and restricted neck rotation; patients examined in the present study also show a severe hearing defect. Additionally the existence of cervical vertebral malformations are revealed, responsible for the rigid neck and the development of scoliosis.
Increased Expression of the Na+/I− Symporter in Cultured Human Thyroid Cells Exposed to Thyrotropin and in Graves’ Thyroid Tissue*
Authors: Saito Tsukasa , Endo Toyoshi , Kawaguchi Akio , Ikeda Masato , Nakazato Minoru , Kogai Takahiko , Onaya Toshimasa 
Published: January 2014

Abstract
The Na+/I− symporter (NIS) is important in hormone synthesis in the thyroid gland. NIS activity, as reflected by I− uptake, was increased by TSH (1 mU/mL) or forskolin (10μ mol/L) in primary cultured human thyroid cells. Northern blot analysis revealed that incubation of these cells with TSH or forskolin for 24 h increased the abundance of NIS messenger ribonucleic acid (mRNA) 2.3- and 2.5-fold, respectively. Immunoblot analysis revealed 2.7- and 2.4-fold increases, respectively, in the amount of NIS protein after 48 h, suggesting that elevated levels of intracellular cAMP induced the expression of NIS in human thyrocytes. We then studied the levels of NIS mRNA and protein in Graves’ thyroid tissue and found that the amount of NIS mRNA in thyroid tissue from individuals with Graves’ disease (n = 5) was 3.8 times that in normal thyroid tissue (n = 5). The abundance of NIS mRNA was significantly correlated with that of thyroid peroxidase or thyroglobulin mRNAs, but not with that of TSH receptor mRNA, in the Graves’ and normal thyroid tissue specimens. The amount of NIS protein was also increased 3.1-fold in Graves’ thyroid tissue compared with that in normal thyroid tissue. The increased expression of NIS may thus contribute to the development of Graves’ disease.
Liposomal Thyroxine: A Noninvasive Model for Transplacental Fetal Therapy*
Authors: Bajoria Rekha , Fisk Nicholas M. , Contractor Soli F. 
Published: January 2014

Abstract
Drugs that cross the placenta sparingly are currently given directly to the fetus by invasive procedures. We investigated whether anionic small unilamellar (SUV) liposomes of different lipid compositions enhanced the transfer and uptake of T4 in an in vitro model of perfused human term placenta. T4-encapsulated anionic liposomes were prepared using lecithin (F-SUV) or distearoyl phosphatidylcholine (S-SUV) with cholesterol and dicetylcholine. The size distribution, encapsulation efficiency, and stability were determined in blood-based media. The transfer kinetics of free and liposomally encapsulated T4 were studied in a dually perfused isolated lobule of human term placenta, with creatinine and liposomal carboxyfluorescein as marker substances. Concentrations of T4 and rT3 were measured by RIA. T4 crossed the placenta sparingly (1.9 ± 0.5%) because it was metabolized to rT3 (9.2 ± 1.3%). Transplacental transfer of T4 was significantly increased by F-SUV (15.8 ± 2.1%; P &lt; 0.001) and S-SUV liposomes (7.1 ± 1.2%; P &lt; 0.001), with a concomitant decrease in fetal rT3 levels (P &lt; 0.001). Placental uptake of F-SUV (13.5 ± 2.0%; P &lt; 0.001) was greater than that of S-SUV liposomes (6.7 ± 0.8%; P &lt; 0.001). Our data suggest that anionic liposomes increase transplacental transfer of T4. If confirmed in vivo, liposomes may provide an alternative noninvasive method of drug delivery to the fetus.
Both Hypothyroidism and Hyperthyroidism Enhance Low Density Lipoprotein Oxidation*
Authors: Sundaram Vidya , Hanna Atef N. , Koneru Lata , Newman H. A. I. , Falko James M. 
Published: January 2014

AbstractHypothyroidism is frequently associated with hypercholesterolemia and an increased risk for atherosclerosis, whereas hyperthyroidism is known to precipitate angina or myocardial infarction in patients with underlying coronary heart disease. We have shown previously that l-T4 functions as an antioxidant in vitro and inhibits low density lipoprotein (LDL) oxidation in a dose-dependent fashion. The present study was designed to evaluate the changes in LDL oxidation in subjects with hypothyroidism and hyperthyroidism. Fasting blood samples for LDL oxidation analyses, lipoprotein determinations, and thyroid function tests were collected at baseline and after the patients were rendered euthyroid. The lag phase (mean ± sem hours) of the Cu+2-catalyzed LDL oxidation in the hypothyroid state and the subsequent euthyroid states were 4 ± 0.0.65 and 14 ± 0.68 h, respectively (P &lt; 0.05). The lag phase during the hyperthyroid phase was 6 ± 0.55 h, and that during the euthyroid phase was 12 ± 0.66 h (P &lt; 0.05). The total and LDL cholesterol levels were higher in hypothyroidism than in euthyroidism and were lower in hyperthyroidism than in the euthyroid state. We conclude that LDL has more susceptibility to oxidation in both the hypothyroid and hyperthyroid states. Thus, the enhanced LDL oxidation may play a role in the cardiac disease process in both hypothyroidism and hyperthyroidism.
Omeprazole: Calcitonin Stimulation Test for the Diagnosis Follow-Up and Family Screening in Medullary Thyroid Carcinoma
Authors: Erdoğan Murat Faik , Güllü Sevim , Başkal Nilgün , Uysal Ali Riza , Kamel Nuri , Erdoğan Gürbüz i 
Published: January 2014

Abstract
Medullary thyroid carcinoma (MTC) occurs sporadically but may also be inherited as part of the multiple endocrine neoplasia (MEN) type 2 syndrome. Screening of the patients and first degree relatives annually with basal and provocative tests for serum immunoreactive calcitonin (CT) levels is essential and enables potentially curative disease. Pentagastrin and calcium are the usual provocative agents used worldwide. We used endogenous gastrin (GT) release achieved by omeprazole, 20 mg b.i.d., to stimulate CT in 9 MTC, in 3 MEN 2A family members, and in 50 healthy control subjects. A steady and significant increase both in GT and CT levels was achieved in 9 MTC patients and 3 of the 14 family members tested, whereas in healthy controls the CT increase stimulated by GT was insignificant.
Preliminary results showed that this new, safe, cheap, and outpatient-basis test can be used in MTC diagnosis, follow-up, and screening.
Deuterium and Bromide Dilution, and Bioimpedance Spectrometry Independently Show That Growth Hormone-Deficient Adults Have an Enlarged Extracellular Water Compartment Related to Intracellular Water
Authors: van Marken Lichtenbelt Wouter D. , Snel Yvonne E. M. , Brummer Robert-Jan M. , Koppeschaar Hans P. F. 
Published: January 2014

Abstract
GH has a strong influence on body composition. However, the effects of GH deficiency in adults on water compartments are not well understood. Therefore, extracellular water (ECW) and total body water were independently determined by deuterium and bromide dilution and by bioimpedance spectrometry in GH-deficient (GHD) adults and compared to those in controls, matched for age, sex, body weight, and height.
The results show that the percent body fat was significantly (P &lt; 0.05) higher, and total body water and intracellular water (ICW) were significantly lower in GHD adults for males, females, and both sexes combined. ECW was not significantly different between the two groups. ECW/ICW in GHD adults (0.42 ± 0.03) was significantly (P &lt; 0.01) higher than that in controls (0.39 ± 0.02). There was a significant positive relation between the ECW/ICW ratio and the percent body fat. These results were confirmed by the bioimpedance spectrometry measurements.
Altered Expression of Fibroblast Growth Factor Receptors in Human Pituitary Adenomas
Authors: Abbass S. Ali Asghar , Asa Sylvia L. , Ezzat Shereen 
Published: January 2014

AbstractWe have shown that basic fibroblast growth factor (FGF) is heterogeneously expressed by human pituitary adenomas and may be implicated as a growth stimulus for these tumors. There are four mammalian FGF receptor (FGFR) genes encoding a complex family of transmembrane tyrosine kinases. The prototypic receptor is composed of three Ig-like extracellular ligand-binding domains, a transmembrane domain, and a cytoplasmic split tyrosine kinase. Multiple forms of cell-bound or secretable isoforms of FGFR-1, -2, and -3 can be generated by cell- and tissue-specific alternative splicing, resulting in tissue-specific FGF function. Shifts in isoform expression accompany tumor progression in some systems.We examined the normal human adenohypophysis and 40 pituitary adenomas to determine the pattern of FGFR expression by reverse transcription-PCR; all tumors were characterized clinically and morphologically. Ribonucleic acid (RNA) was extracted from frozen tumor tissue and primers were used to distinguish messenger RNA of the secretable first Ig-like domain (I) and those of the transmembrane and kinase domains (K) of each FGFR subtype. The normal pituitary-expressed mRNAs for FGFR-1 I and K, FGFR-2 I and K, FGFR-3 I and K, and FGFR-4 I but not FGFR-4 K; this represents the first report of a truncated isoform of FGFR-4, indicating possible alternative polyadenylation sites in this receptor. Only 3 tumors had the same pattern of expression of the 4 FGFRs as the normal gland. Although all tumors expressed FGFR-1 I, 1 tumor did not express FGFR-1 K, suggesting the production of only a secretable form of FGFR-1 by this tumor. Four tumors were negative for FGFR-2 I and K; 6 expressed the secretable form only, and 17 expressed FGFR-2 K but not I. All tumors expressed FGFR-3 I; 14 had secretable forms only, and no tumors expressed FGFR-3 K alone. As in the normal gland, 13 tumors expressed only the secretable I form of FGFR-4. Unlike the normal pituitary, however, 22 expressed FGFR-4 I and K, indicating a possible tumor-specific transmembrane receptor. Five tumors were negative for FGFR-4 I and K. Expression of FGFR proteins was confirmed by immunohistochemical localization of the C-terminal portion of FGFR-1, -2, -3, and -4; the results correlated with the RNA data in each case. There was no correlation between tumor type, size, or aggressiveness and the expression pattern of FGFRs.Our study suggests that pituitary adenomas have altered FGFR subtype and isoform expression, which may determine their hormonal and proliferative responses to FGFs.
Idiopathic Hypothalamic Diabetes Insipidus, Pituitary Stalk Thickening, and the Occult Intracranial Germinoma in Children and Adolescents*
Authors: Mootha Sudha L. , Barkovich Anthony J. , Grumbach Melvin M. , Edwards Michael S. , Gitelman Stephen E. , Kaplan Selna L. , Conte Felix A. 
Published: January 2014

Abstract
We report nine consecutive children and adolescents [five females and four males; aged 2 yr 8 months (m) to 18 yr 1 m] studied over the last 5 yr with idiopathic central diabetes insipidus. In addition to vasopressin deficiency, anterior pituitary hormone deficiencies were detected, either on evaluation at presentation or during follow-up studies over the following 3 yr. Four patients had an increased concentration of plasma PRL. One patient had multiple pituitary hormone deficiencies at diagnosis, and two others developed the same by 21 m of follow-up. Brain magnestic resonance imaging scans, performed at presentation, were originally interpreted as normal in four of nine patients, except for absence of the bright posterior pituitary signal; after retrospective review, two of nine were considered normal. All of the brain magnetic resonance imaging (MRI) scans showed positive findings by 14 m of follow-up. The first abnormal finding in all patients was isolated pituitary stalk thickening. Evaluation of cerebrospinal fluid (CSF) for hCG was positive in three of eight evaluated patients; the three positive CSF values were found at presentation and 3 and 9 m after presentation. All eight patients assessed were negative for CSF α-fetoprotein and cytology, and no patient had serum tumor markers. Transsphenoidal biopsy of the lesion in seven of nine patients showed a germinoma in six patients and inflammatory cells in one. The six patients with documented germinoma comprise 31% of the intracranial germinomas diagnosed in this age group at the University of California-San Francisco during the last 5 yr. The patient with mononuclear inflammatory cells on biopsy along with one other patient have had spontaneous resolution of their stalk thickening. So-called “idiopathic” central diabetes insipidus warrants close follow-up to determine the etiology, especially if anterior pituitary hormone deficiencies are detected. Normal brain MRI scans or scans that show isolated pituitary stalk thickening merit follow-up with serial contrast enhanced brain MRI for the early detection of an evolving occult hypothalamic-stalk lesion. CSF evaluation is recommended at presentation because elevated CSF hCG may precede MRI abnormalities.
Ex Vivo Expansion of Human Pancreatic Endocrine Cells1
Authors: Beattie Gillian M. , Cirulli Vincenzo , Lopez Ana D. , Hayek Alberto 
Published: January 2014

AbstractCell transplantation as a therapy for type 1 diabetes is facilitated by ex vivo cell expansion of pancreatic β-cells without loss of differentiative characteristics. The aim of this study was to determine the optimal conditions for in vitro growth of functional human pancreatic endocrine tissue. We examined the mitogenicity of matrixes from a variety of cell lines; proliferation was greater in cells growing on matrixes from bladder carcinoma cell lines, especially in monolayers grown on matrix from the human cell line HTB-9. After 14-day culture, there was a more than 100-fold proliferative increase, which was augmented to a more than 200-fold when hepatocyte growth factor/scatter factor was added; however, hepatocyte growth factor/scatter factor induced a rapid decrease in insulin content. Without the growth factor, fetal cell monolayers expanded 4-fold with no insulin loss; however, after 12-fold expansion, the insulin levels decreased to 40% of those in unexpanded cells. Adult islet cells expanded 3-fold without insulin loss. After 5-fold expansion, insulin levels decreased by 25% compared to those in free floating islets while retaining a normal response to secretagogues. Together, these results indicate that HTB-9 matrix provides the best stimulatory effect on replication of human endocrine cells, with little loss of in vitro function.
Serum Leptin Levels in Women with Polycystic Ovary Syndrome: The Role of Insulin Resistance/ Hyperinsulinemia1
Authors: Laughlin G. A. , Morales A. J. , Yen S. S. C. 
Published: January 2014

Abstract
Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (SI) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P &lt; 0.0001), and SI was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-α hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P &lt; 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P &lt; 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P &lt; 0.001) as compared with NC.
Serum leptin levels for PCOS (24.1 ± 2.6 ng/mL) did not differ from NC (21.5 ± 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P &lt; 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P &lt; 0.0001 for both PCOS and NC) and negatively with SI and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P &lt; 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.
Gender Differences in Both Spontaneous and Stimulated Leptin Secretion by Human Omental Adipose Tissue in Vitro: Dexamethasone and Estradiol Stimulate Leptin Release in Women, But Not in Men1
Authors: Casabiell Xesús , Piñeiro Verónica , Peino Roberto , Lage Mary , Camiña Jesús , Gallego Rosalía , Vallejo Luis Garcia , Dieguez Carlos , Casanueva Felipe F. 
Published: January 2014

Leptin is a hormone secreted by the adipocytes to serve as a signal to the central nervous system to regulate energy homeostasis. Circulating leptin mainly reflects both total fat mass and the size of constituent adipocytes, although other ancillary hormonal factors may contribute to its blood concentration. Relevant gender differences in leptin concentrations have been reported, but it is not clear whether the elevated leptin levels in women are an intrinsic property of their adipocytes or merely reflect a greater amount of fat reserves.To clarify these points, a systematic study with organ culture from human omental adipose tissue either stimulated or not with steroid hormones was undertaken in samples obtained at surgery from 67 nonobese donors (33 women and 34 men). The assay was standardized in periods of 24 h ending at 96 h, with no apparent tissue damage. Each adipose tissue sample from a single donor was incubated in triplicate, and leptin results are expressed as the mean ± sem of the integrated secretion to the medium (area under the curve; nanograms of leptin per g tissue/48 h).Control nonstimulated samples showed a steady leptin secretion along the 96 h studied, with the peak of secretory activity reached at 48 h; afterward, the in vitro secretion reached a plateau state. Spontaneous leptin secretion in samples from 33 women (3904 ± 347) was significantly higher (P &lt; 0.05) than that in samples from 34 men (2940 ± 323). Coincubation of adipose tissue with 1 μmol/L dexamethasone induced a clear-cut leptin increase (P &lt; 0.05) in samples from women (5848 ± 624; n = 12), but did not change the spontaneous release of leptin in samples from men (3353 ± 741; n = 6). Similarly, coincubation of adipose tissue with 1 μmol/L estradiol induced a notable leptin increase (P &lt; 0.05) in samples from women (5698 ± 688; n = 9), whereas it did not alter the secretion in the male samples (3373 ± 444; n = 6). In samples from both sexes, coincubation with 1 μmol/L estrone or progesterone had no effect, whereas 1 μmol/L forskolin significantly (P &lt; 0.05) reduced leptin release.In conclusion, leptin secretion from omental adipose tissue in vitro 1) is significantly higher in samples from women than in samples from men, 2) is stimulated by dexamethasone and estradiol in women but not in men, 3) is not modified by progesterone or estrone in both sexes, and 4) is inhibited by forskolin in both genders. This different response to the stimulation of adipose tissue may be the biological basis for the gender differences observed in circulating levels of human leptin.
Modest Hormonal Effects of Soy Isoflavones in Postmenopausal Women*
Authors: Duncan Alison M. , Underhill Kerry E.W. , Xu Xia , LaValleur June , Phipps William R. , Kurzer Mindy S. 
Published: January 2014

Abstract
Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to body weight[ control: 0.11 ± 0.01; low isoflavone (low-iso): 1.00 ± 0.01; high isoflavone (high-iso): 2.00 ± 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36–38, 64–66, and 92–94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.