bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Leptin Concentrations and Cardiac Autonomic Nervous System in Healthy Subjects with Different Body Weights
Authors: Paolisso Giuseppe , Manzella Daniela , Montano Nicola , Gambardella Antonio , Varricchio Michele
Published: January 2014

Previous studies have shown that leptin stimulates sympathetic nervous system; heart rate variability (HRV) is a widely used technique for assessing the sympathovagal balance at the cardiac level. The aim of our study was to investigate a possible relationship between plasma leptin levels and the autonomic regulation using spectral analysis of HRV. In 120 healthy nonobese subjects the plasma leptin concentration was determined, and HRV was recorded at baseline and during tilt. All subjects were categorized in quartiles of plasma leptin concentration. Analysis of data showed a significant increase in body mass index, body fat, fasting plasma insulin, triglyceride concentration, and homeostatic model assessment values throughout the different quartiles of plasma leptin concentration. Concerning cardiovascular parameters, heart rate, arterial blood pressures, and RR intervals were not significantly different among the quartiles. Total power and high frequency (HF) in normalized units were significantly decreased, whereas low frequency (LF) normalized units was progressively increased from the first to the fourth quartile. Thus, the LF/HF ratio rose gradually and significantly from the lowest to the highest quartile. Such results were independent of the body fat estimate (P < 0.03 for the trend). The change in the LF/HF ratio was significantly enhanced during tilt (P < 0.001 vs. rest values for all quartiles); the effect was stronger in subjects in the fourth quartile of plasma leptin concentration (P < 0.005 for the trend). The latter parameter was also independent of body fat content and distribution (P < 0.01). Our study shows that increasing fasting plasma leptin concentrations are associated with a shift of the sympathovagal balance toward a progressive increase in sympathetic activation and an increased response to orthostatic stimulus in nonobese subjects with different body fat contents.
Reduced Parathyroid Vitamin D Receptor Messenger Ribonucleic Acid Levels in Primary and Secondary Hyperparathyroidism*
Authors: Carling Tobias , Rastad Jonas , Szabó Eva , Westin Gunnar , Åkerström Göran
Published: January 2014

Vitamin D, via its receptor (VDR), inhibits the hormone secretion and proliferation of parathyroid cells. Vitamin D deficiency and reduced parathyroid VDR expression has been associated with development of hyperparathyroidism (HPT) secondary to uremia. VDR polymorphisms may influence VDR messenger RNA (mRNA) levels and have been coupled to an increased risk of parathyroid adenoma of primary HPT. VDR mRNA relative to glyceraldehyde-3-phosphate dehydrogenase mRNA levels were determined by RNase protection assay in 42 single parathyroid adenomas of patients with primary HPT, 23 hyperplastic glands of eight patients with uremic HPT, and 15 normal human parathyroid glands. The adenomas and hyperplasias demonstrated similar VDR mRNA levels, which were reduced (42 ± 2.8% and 44 ± 4.0%) compared with the normal glands (P < 0.0001). Comparison of parathyroid adenoma with a normal-sized parathyroid gland of the same individual (n = 3 pairs) showed a 20–58% reduction in the tumor. Nodularly enlarged glands represent a more advanced form of secondary HPT and showed greater reduction in the VDR mRNA levels than the diffusely enlarged glands (P < 0.005). The reduced VDR expression is likely to impair the 1,25(OH)2D3-mediated control of parathyroid functions, and to be of importance for the pathogenesis of not only uremic but also primary HPT. Circulating factors like calcium, PTH, and 1,25(OH)2D3 seem to be less likely candidates mediating the decreased VDR gene expression in HPT.
Pseudohypoparathyroidism 1b: Exclusion of Parathyroid Hormone and Its Receptors as Candidate Disease Genes1
Authors: Jan de Beur Suzanne M. , Ding Chang-Lin , LaBuda Michele C. , Usdin Ted B. , Levine Michael A.
Published: January 2014

Pseudohypoparathyroidism 1b (PHP 1b) is characterized by specific resistance of target tissues to PTH, but no mutations in the PTH/PTH-related peptide (PTHrP) receptor gene have been identified. To investigate the basis for defective PTH signaling, we used polymorphic markers in or near the genes encoding PTH and its receptors to perform linkage analysis between these loci and PHP 1b. Two multiplex PHP 1b families (families M and K) were informative for an intragenic polymorphism in exon 13 of the PTH/PTHrP receptor gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. Linkage analysis revealed discordance of the PTH/PTHrP receptor with PHP1b. One PHP 1b kindred (family M) was informative for a intragenic polymorphism in exon 3 of the PTH gene detected by PCR amplification and resolved by denaturing gradient gel electrophoresis. The PTH gene polymorphism segregation was discordant with PHP 1b. Probands from each family had normal PTH genes by direct sequence analysis. In three PHP 1b kindreds, we analyzed simple sequence polymorphisms in three microsatellite markers flanking the PTH type 2 receptor locus located at 2q33. Linkage analysis demonstrated no linkage. In conclusion, neither the PTH gene nor the PTH receptor genes (type 1 and 2) are linked to PHP 1b.
A Comparison of the Effects of Raloxifene and Estrogen on Bone in Postmenopausal Women1
Authors: Prestwood Karen M. , Gunness Michele , Muchmore Douglas B. , Lu Yili , Wong Mayme , Raisz Lawrence G.
Published: January 2014

Raloxifene HCl, a selective estrogen receptor modulator, has been shown to increase bone mineral density (BMD) and decrease biochemical markers of bone turnover in postmenopausal women without stimulatory effects on the breast and uterus. However, it is not known whether the changes in BMD and bone turnover are associated with changes at the tissue level, nor how changes with raloxifene compare with estrogen. In this randomized, double blind study, we evaluated the effects of raloxifene (Evista, 60 mg/day) or conjugated equine estrogens (CEE; Premarin, 0.625 mg/day) on bone architecture, bone turnover, and BMD. Iliac crest bone biopsies were obtained at baseline and at the end of the study after double tetracycline labeling and were analyzed for standard histomorphometric indexes. Serum and urinary biochemical markers of bone turnover were measured at baseline and at 4, 10, 18, and 24 weeks of treatment. Total body, lumbar spine, and hip BMD were measured at baseline and at the end of the study by dual energy x-ray absorptiometry.

Activation frequency and bone formation rate/bone volume were significantly decreased from baseline in the CEE, but not in the raloxifene, group. Bone mineralization did not change in either group. Most markers of bone resorption and formation decreased in both groups, but to a greater degree in the CEE group (P < .05). Total body and lumbar spine BMD increased from baseline in both groups, with a greater increase in the CEE group (P< 0.05). Hip BMD significantly increased from baseline in the raloxifene group, but the change was not different from that in the CEE group. These results suggest that raloxifene reduces bone turnover and increases bone density, although to a lesser extent than CEE. Thus, raloxifene is an alternative to CEE for the prevention and treatment of osteoporosis in postmenopausal women.
Management of the Solitary Thyroid Nodule: Results of a North American Survey1
Authors: Bennedbæk Finn Noe , Hegedüs Laszlo
Published: January 2014

The present survey evaluated current trends in the management of the nontoxic solitary thyroid nodule by expert endocrinologists in North America and compared their results with a similar European Thyroid Association survey. A questionnaire was circulated to all clinical members of the American Thyroid Association. An index case (a 42-yr-old woman with a solitary 2 × 3-cm thyroid nodule and no clinical suspicion of malignancy) and 11 variations were provided to evaluate how each alteration would affect management. One hundred and seventy-eight members replied and 142 responses were retained for analysis, corresponding to a response rate of 43% of clinically active members. Based on the index case, basal serum TSH was the routine choice of 99%, and serum T4 and/or free T4 were included by 61% of the respondents. Thyroid peroxidase antibodies and serum calcitonin were included by 30% and 5%, respectively. Thyroid scintigraphy was used by 23% (123I, 63%; 99mTc, 31%; 131I, 6%), and ultrasonography was used by 34%. Fine needle aspiration biopsy was routinely used by all and was guided by palpation in 87%. Based on the individually chosen diagnostic tests indicating a benign solitary thyroid nodule in a euthyroid subject, l-T4 treatment was advocated by 47%, no specific treatment and follow-up was advocated by 52%, and surgery was advocated by 1%. Clinical factors suggesting thyroid malignancy (e.g. rapid nodule growth and a large nodule of 5 cm) lead a significant number of clinicians (40 - 50%; P < 0.00001) to disregard biopsy results and to choose a surgical strategy. Nevertheless, North American endocrinologists heavily rely on fine needle aspiration biopsy results. Compared to the European Thyroid Association survey, North American endocrinologists use imaging [scintigraphy, 23% vs. 66% (P < 0.0001); ultrasonography, 34% vs. 80% (P < 0.0001)] and serum calcitonin (5% vs. 43%; P < 0.0001) less frequently. A nonsurgical strategy prevails in North America, and despite controversies on the effect of l-T4, this treatment is supported by more than 40% in both Europe and North America.
High Expression of Somatostatin Receptors and Messenger Ribonucleic Acid for Its Receptor Subtypes in Organ-Confined and Locally Advanced Human Prostate Cancers1
Authors: Halmos Gabor , Schally Andrew V. , Sun Baodong , Davis Rodney , Bostwick David G. , Plonowski Artur
Published: January 2014

To evaluate the potential application of somatostatin (SST) analogs as an adjuvant treatment for prostate cancer, we characterized the binding sites for SST octapeptide analogs on prostate cancers in patients treated with radical prostatectomy. The affinity and density of binding sites for SST analog RC-160 on 80 surgical specimens of prostate cancers were determined by ligand competition assays. The expression of messenger ribonucleic acid (mRNA) for SST receptor subtype 1 (SSTR1), subtype 2 (SSTR2), and subtype 5 (SSTR5) was also investigated in 22 samples by RT-PCR. Fifty-two of 80 specimens (65%), showed a single class of specific binding sites for RC-160 with a mean dissociation constant (Kd) of 9.44 nmol/L and a mean maximal binding capacity of 754.8 fmol/mg membrane protein. The mRNA for SSTR1 was detected in 86% of samples, whereas the incidences of mRNA for SSTR2 and SSTR5 were 14% and 64%, respectively. The expression of SSTR2 and/or SSTR5 was 100%, consistent with the presence of RC-160 binding. In patients at high risk of cancer recurrence (stage pT3 and/or Gleason score of 8–10), the incidence of RC-160 binding (65.7%) was similar to that observed in the low risk group (64.3%). The demonstration of the high incidence of octapeptide-preferring SSTRs in organ-confined and locally advanced prostate cancers supports the merit of further investigations of the application of SST analogs and their radionuclide and cytotoxic derivatives for adjuvant treatment of patients at high risk of cancer recurrence after radical prostatectomy. Such approaches could be also considered for patients with advanced prostate cancer at the time of relapse.
Dynamic Changes in the Intrafollicular Inhibin/Activin/Follistatin Axis during Human Follicular Development: Relationship to Circulating Hormone Concentrations*
Authors: Schneyer Alan L. , Fujiwara Toshihiro , Fox Janis , Welt Corrine K. , Adams Judith , Messerlian Geralyn M. , Taylor Ann E.
Published: January 2014

Previous studies of normal human ovaries suggest that inhibins, activins, and follistatin (FS) are produced in a stage-specific pattern indicative of intraovarian, autocrine/paracrine roles in regulating follicle development. However, these studies relied largely on surgical specimens and thus include little information about the menstrual cycle stage or dominant follicle status at the time follicles or ovaries were obtained. The purpose of this study was to 1) determine the pattern of intrafollicular hormone biosynthesis across antral follicle development in normal women, 2) compare hormone concentrations in dominant and nondominant follicles from the same ovary, and 3) examine the relationship between dominant follicle hormone content and circulating hormone levels. Intrafollicular estradiol, progesterone, and inhibin A concentrations increased significantly with follicle size or maturity, whereas significant inverse relationships were observed for androstenedione and the androstenedione/estradiol (A:E) ratio. In contrast, neither inhibin B, activin A, nor free FS varied consistently with size or maturity. Estradiol, progesterone, and inhibin A levels and A:E ratio were significantly lower in nondominant follicles compared to the dominant follicle aspirated from the same ovary. Although intrafollicular and serum concentrations of each hormone followed the same general pattern as follicles develop, the human follicular fluid/serum gradients changed during the follicular phase and were different for estradiol and inhibin A, suggesting the presence of stage-specific differences in pharmacodynamics. These results are consistent with the hypothesis that the orderly transition from an activin-dominant to an inhibin A/FS-dominant microenvironment is critical for dominant follicle development.
Anisomastia Associated with Interstitial Duplication of Chromosome 16, Mental Retardation, Obesity, Dysmorphic Facies, and Digital Anomalies: Molecular Mapping of a New Syndrome by Fluorescent in Situ Hybridization and Microsatellites to 16q13 (D16S419-D16S503)*
Authors: Stratakis Constantine A. , Lafferty Antony , Taymans Susan E. , Gafni Rachel I. , Meck Jeanne M. , Blancato Jan
Published: January 2014

Anisomastia is a common problem among developing adolescent girls. We recently evaluated a 22-yr-old female patient who had severe anisomastia (which had been repaired by surgery), associated with moderate to severe mental retardation, a stocky body habitus with mild obesity, dysmorphic facies (prominent, upslanting palpebral fissures, beaked nose, and a prominent philtrum), webbed neck, low hairline, and severe bilateral clinodactyly of the third, fourth, and fifth fingers with acral (but not large joint) flexion contractures. A peripheral blood high resolution karyotype revealed additional chromosomal material within the long arm of chromosome 16. Densitometric analysis of amplified polymorphic sequence-tagged sites (STS) mapping to 16q suggested that the duplication is defined by the noninvolved markers D16S419 [16q12-cen, 66 centimorgan (cM) from 16p terminus] and D16S421 (16q13-q21, 84.4 cM), encompassing a maximum of 18.4 cM of genetic distance. The STS analysis showed that the duplication was on the maternally derived chromosome 16, resulting in two maternal (and one paternal) copies of that region of chromosome 16. The location was further confirmed by bacterial artificial chromosomes (BACs) that were obtained from a commercially available library, labeled, and used for fluorescence in situ hybridization. The BACs containing STSs D16S408, D16S3137, and D16S3032 (markers that correspond to 16q13) showed two regions of hybridization, indicating that these sites were duplicated, whereas a BAC containing the STS D16S512 (which corresponds to 16q21-q22) revealed one hybridization signal per 16q, indicating that the corresponding region was not involved in the duplication. The distance between the probe signals suggested a tandem duplication. We conclude that even though trisomy 16 is the most common autosomal trisomy in spontaneous abortions, few patients with unbalanced chromosome 16 abnormalities survive to adulthood; in this report we describe one such patient with an interstitial chromosome 16 duplication (at 16q13), who had a specific phenotype associated with abnormal breast size. There are clinical similarities between this patient and patients with other 16q abnormalities, although the breast findings were unique. Molecular cytogenetics, including fluorescence in situ hybridization and densitometric analysis of amplified STSs, provided useful tools for the precise mapping of the syndrome to 16q13, where the gene(s) responsible for this phenotype might be localized.
Increased Fibrinogen Production in Type 2 Diabetic Patients without Detectable Vascular Complications: Correlation with Plasma Glucagon Concentrations
Authors: Barazzoni R. , Zanetti M. , Davanzo G. , Kiwanuka E. , Carraro P. , Tiengo A. , Tessari P.
Published: January 2014

Fibrinogen is a strong cardiovascular risk factor in the general population, and increased fibrinogen plasma concentrations have been reported in type 2 diabetic patients. However, the mechanisms leading to hyperfibrinogenemia in type 2 diabetes are not known. It is also not known whether possible alterations of fibrinogen turnover may precede clinical diabetic micro- and macrovascular complications and therefore potentially contribute to their onset. To address these questions, fibrinogen production was determined in six male type 2 diabetic patients without detectable micro- and macrovascular complications (age, 45 ± 4 yr; body mass index, 27 ± 0.9 kg/m2) and in seven nondiabetic matched controls using leucine isotope precursor-product relationships. Plasma glucose (P < 0.001), insulin (P < 0.05), and glucagon concentrations (P < 0.01) were increased in the patients. Diabetic patients also had increased plasma fibrinogen concentration (+∼50%; P < 0.01) and pool (+∼40%; P < 0.01) as well as fractional (+∼35%; P = 0.08) and absolute (+∼100%; P < 0.01) synthetic rates. The plasma glucagon concentration was positively related (P < 0.005 or less) to the fibrinogen concentration as well as to fractional and absolute synthetic rates. Thus, fibrinogen production is markedly enhanced, and this alteration is likely to determine the observed hyperfibrinogenemia in type 2 diabetic patients. Hyperglucagonemia may contribute to the increased fibrinogen production. These findings in normoalbuminuric patients without clinical complications support the hypothesis that increased fibrinogen production and plasma concentrations may precede and possibly contribute to the onset of clinical cardiovascular complications in type 2 diabetes.
Prognostic Markers in Patients with Typical Bronchial Carcinoid Tumors*
Authors: Granberg Dan , Wilander Erik , Öberg Kjell , Skogseid Britt
Published: January 2014

Typical bronchial carcinoids are usually considered fairly benign tumors. Metastases do however occur, and up to 10% of the patients ultimately die from their disease. To identify prognostic markers, we immunostained 43 typical bronchial carcinoids with antibodies against 8 possibly relevant hormones, oncogenes, tumor suppressor genes, adhesion molecules, and proliferation markers. Altogether 12 patients (28%) had metastatic disease, of whom 10 had regional lymph node metastases at diagnosis. Distant metastases have occurred in 5 patients (12%); all of these have died from their disease. Patients with high expression of Ki-67 had shorter survival time (P < 0.01). None of the immunostained hormones correlated to distant metastases or shorter survival time, but gastrin-releasing peptide correlated to metastatic disease (P < 0.05). All patients who died had CD44-negative tumors (P < 0.001). Nuclear nm23 staining correlated to decreased risk for metastatic disease and distant metastases per se (P < 0.01). Bcl-2 and p53 were associated with increased risk for distant metastases (P < 0.05 and P < 0.01, respectively). We conclude that some patients with typical bronchial carcinoids die from their disease and that gastrin-releasing peptide, Bcl-2, and p53 may be of importance for the malignant transformation of the tumor. Moreover, CD44, nm23, and Ki-67 may give valuable prognostic information and help identify the patients at risk of disease-related death.
Studies of the Synergistic Effect of the Trp/Arg64 Polymorphism of theβ 3-Adrenergic Receptor Gene and the −3826 A→G Variant of the Uncoupling Protein-1 Gene on Features of Obesity and Insulin Resistance in a Population-Based Sample of 379 Young Danish Subjects*
Authors: Urhammer Søren A. , Hansen Torben , Borch-Johnsen Knut , Pedersen Oluf
Published: January 2014

This study examined whether the simultaneous presence of the previously identified Trp/Arg64 polymorphism of theβ 3-adrenergic receptor (BAR) gene and the −3826 A→G nucleotide variant of the uncoupling protein-1 (UCP1) gene are associated with obesity, insulin resistance, or alterations in size at birth in a Danish study population comprising 379 unrelated young Caucasian subjects. All study participants underwent an iv glucose tolerance test with addition of tolbutamide after 20 min. In addition, a number of biochemical and anthropometric measures were performed on each subject. The subjects were genotyped for the 2 polymorphisms by applying PCR-restriction fragment length polymorphism. The subjects were divided into 4 groups according to their BAR and UCP1 genotype: wild-type carriers (n = 184), only Trp/Arg64 carriers (n = 29), only A→G UCP1 carriers (n = 146), and carriers of both genetic variants (n = 20). There were no differences across the genotype groups with respect to body mass index, fat mass, waist to hip ratio, birth weight or length, ponderal index, or weight gain during childhood or adolescence, nor was the combined genotype related to alterations in fasting serum levels of lipids, insulin, or C peptide or the insulin sensitivity index. In conclusion, the present study failed to demonstrate an additive or synergistic effect of the Trp/Arg64 variant of the BAR gene and the −3826 A→G variant of the UCP1 gene on the development of obesity and insulin resistance among randomly recruited Danish Caucasian subjects.
Ontogenetic Pattern of Thyroid Hormone Receptor Expression in the Human Testis
Authors: Jannini Emmanuele A. , Crescenzi Anna , Rucci Nadia , Screponi Emiliano , Carosa Eleonora , De Matteis Anna , Macchia Enrico , d’Amati Giulia , D’Armiento Massimino
Published: January 2014

We studied the spatiotemporal distribution of thyroid hormone nuclear receptors (TRs) α1 and α2 and β messenger RNA (mRNA) levels in normal human testicular tissue during development and in adulthood. Nonpathological specimens from five aborted fetuses (17 and 23 weeks of gestation, three and two cases, respectively) and from four patients undergoing orchiectomy (18 months old and 38-, 42-, and 52-yr-old, respectively) were analyzed by Northern blot, semiquantitative RT-PCR amplification using DNA sequences or specifically designed primers for the TR isoforms, and in situ hybridization.

By using PCR amplification, we found that TRα1 and TRα2 are both expressed at different levels in fetal and adult testis. At all ages TRα2 is found at higher levels. Northern analysis showed hybridization signals corresponding to the expression of TRα2 and TRα1 in a ratio that increased from 2.6 at 17 weeks of gestation to 12.0 in adulthood. In fact, the expression of TRα1 dramatically decreased throughout development, being faintly detectable in the adult testis. Expression of TRβ was not detected at any age studied. This finding was further confirmed by PCR, which did not amplify TRβ either in fetal or in adult testis mRNAs. In situ hybridization studies showed the absence of TRβ and that TRα1 and TRα2 colocalized in Sertoli cells of prepubertal testis, whereas germ and interstitial cells appeared devoid of TR mRNA signals.

From these results it can be concluded that the human testis exclusively expresses TRα, which is localized in Sertoli cells, TRβ being always undetectable. Fetal and prepubertal ages represent the period of maximal expression of TRα1 and TRα2. Theα 2/α1 ratio rises dramatically after development. These results confirm a critical window for the action of thyroid hormone in human testis, in the period of maximal expression of T3 binding isoform TRα1, and may account for the macroorchidism without virilization occurring when hyposecretion of thyroid hormones occurs before puberty.
Long-Acting Peptidomimergic Control of Gigantism Caused by Pituitary Acidophilic Stem Cell Adenoma*
Authors: Maheshwari Hiralal G. , Prezant Toni R. , Herman-Bonert Vivien , Shahinian Hrayr , Kovacs Kalman , Melmed Shlomo
Published: January 2014

Gigantism is caused by GH hypersecretion occurring before epiphyseal long bone closure and usually is associated with pituitary adenoma. A 15-yr-old female patient presented with accelerated growth due to a large pituitary tumor that was surgically resected to relieve pressure effects. Second surgery to remove residual tumor tissue was followed by administration of octreotide LAR, a long-acting depot somatostatin analog, together with long-acting cabergoline. Height was over the 95th percentile, with evidence of a recent growth spurt. Serum GH levels were more than 60 ng/mL (normal, <10 ng/mL) with no suppression to 75 g oral glucose, and serum PRL (>8000 ng/mL; normal, <23 ng/mL) and insulin-like growth factor I levels (845 ng/mL; age-matched normal, 242–660 ng/mL) were elevated. Histology, immunostaining, and electron microscopy demonstrated a pituitary acidophil stem cell adenoma. Tumor tissue expressed both somatostatin receptor type 2 and dopamine receptor type 2. The Gs α subunit, GHRH receptor, and MEN1 genes were intact, and tumor tissue abundantly expressed pituitary tumor transforming gene (PTTG). Serum GH and PRL levels were controlled after two surgeries, and with continued cabergoline and octreotide LAR GH, PRL, and insulin-like growth factor I levels were normalized. In conclusion, administration of long-acting somatostatin analog every 4 weeks in combination with a long-acting dopamine agonist biweekly controlled biochemical parameters and accelerated growth in a patient with gigantism caused by a rare pituitary acidophil stem cell adenoma.
Antibodies to Glutamic Acid Decarboxylase and Peripheral Nerve Function in Type 1 Diabetes*
Authors: Hoeldtke Robert D. , Bryner Kimberly D. , Hobbs Gerald R. , Horvath Gabriella G. , Riggs Jack E. , Christie Ian , Ganser Gary , Marcovina Santica M. , Lernmark Ake
Published: January 2014

Autoimmune mechanisms have been implicated in the pathophysiology of diabetic neuropathy. We studied the association between glutamic acid decarboxylase (GAD65) and islet cell (IA-2) autoantibodies as well as autoantibodies to the autonomic nervous system and peripheral nerve function in recent onset type 1 diabetes. Thirty-seven patients (27 females and 10 males) enrolled 2–22 months after diagnosis. Humoral factors, glycemic control, and peripheral nerve function were measured annually for 3 yr.

Patients with high GAD65Ab had worse glycemic control and higher insulin requirements. Patients with high GAD65Ab had slower motor nerve conduction velocities in the median, ulnar, and peroneal nerves (P < 0.025 for each nerve). The mean motor nerve conduction velocity Z scores at the time of the third evaluation was 0.341 ± 0.25 for the low GAD65Ab patients and −0.600 ± 0.25 for the high GAD65Ab patients (P < 0.01). Similar differences between the low and high GAD65Ab groups were observed for F wave latencies, thermal threshold detection, and cardiovascular autonomic function. The composite peripheral nerve function Z scores in the low GAD65Ab patients were 0.62 ± 11, 0.71 ± 0.19, and 0.21 ± 0.14 at the first, second, and third evaluations, significantly different from those in the high GAD65Ab patients in whom they were −0.35 ± 0.15, −0.46 ± 0.18, and −0.42 ± 0.16 (P < 0.001).

In summary, GAD65Ab in patients with recent onset type 1 diabetes are associated with worse glycemic control and slightly worse peripheral nerve function. Although the latter remained within normal limits and none of the patients had clinical neuropathy, the GAD65Ab-related differences in composite peripheral nerve function were highly significant (P < 0.001) and could not be attributed to GAD65Ab-related differences in glycemic control.
A Five-Base Pair Deletion in the Sedlin Gene Causes Spondyloepiphyseal Dysplasia Tarda in a Six-Generation Arkansas Kindred*
Authors: Mumm Steven , Christie Paul T. , Finnegan Patrick , Jones Jonathan , Dixon Peter H. , Pannett Anna A. J. , Harding Brian , Gottesman Gary S. , Thakker Rajesh V. , Whyte Michael P.
Published: January 2014

A six-generation kindred from Arkansas with X-linked recessive spondyloepiphyseal dysplasia tarda (SEDT) was investigated by genetic linkage and mutation analysis. SEDT had been mapped on the X-chromosome (Xp22.2), and the clinical and radiographic evolution of this kindred had been published.

Linkage analysis proved informative for all five polymorphic markers tested, and DXS987 and DXS16 co-segregated with the Arkansas kindred (peak logarithm of the odds scores, 3.54 and 3.36, respectively). Subsequently, dinucleotide deletion in a new gene designated “sedlin” was reported to cause SEDT in three families. In an affected man and obligate carrier woman in the Arkansas kindred, we found a 5-bp deletion in exon 5 of sedlin. The defect causes a frameshift, resulting in eight missense amino acids and premature termination. The 5-bp deletion was then demonstrated to segregate with SEDT in the four living generations, including eight affected males and nine obligate carrier females. Furthermore, the deletion was identified in four females who potentially were heterozygous carriers for SEDT. The mutation was not detected in the two young sons of the consultand (believed to be a carrier because of her subtle radiographic skeletal changes and then shown to have the deletion), but they were too young for x-ray diagnosis.

Identification of a defect in sedlin in this SEDT kindred enables carrier detection and presymptomatic diagnosis and reveals an important role for this gene in postnatal endochondral bone formation.
Phenotype-Genotype Correlation in 56 Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
Authors: Deneux Catherine , Tardy Véronique , Dib Anne , Mornet Etienne , Billaud Line , Charron Daniel , Morel Yves , Kuttenn Frédérique
Published: January 2014

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5′-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.
Racial Disparities in Metabolism, Central Obesity, and Sex Hormone-Binding Globulin in Postmenopausal Women1
Authors: Berman Dora M. , Rodrigues Lori M. , Nicklas Barbara J. , Ryan Alice S. , Dennis Karen E. , Goldberg Andrew P.
Published: January 2014

Increased total and intraabdominal fat (IAF) obesity as well as other metabolic conditions associated with the insulin resistance syndrome (IRS) are related to low levels of sex hormone-binding globulin (SHBG) in young and older Caucasian (CAU) and young African-American (AA) women. We examined whether postmenopausal AA women, a population with a high incidence of obesity and IRS despite low IAF, would have higher levels of circulating SHBG compared with CAU women, and whether there would be negative relationships between indexes of obesity and risk factors associated with IRS and SHBG levels. We measured body composition, SHBG, free testosterone, leptin, glucose tolerance, insulin, and lipoprotein lipids in 55 CAU (mean ± sd, 59 ± 7 yr) and 35 AA (57 ± 6 yr) sedentary women of comparable obesity (48% body fat, by dual energy x-ray absorptiometry). Compared with CAU women, AA women had larger waist (101 vs. 96 cm), larger fat mass (44.9 ± 8.8 vs. 39.9 ± 8.1 kg), larger sc fat area (552± 109 vs. 452 ± 109 cm2), and lower IAF/SC ratio (0.28 ± 0.12 vs. 0.38 ± 0.15; P < 0.01), but similar waist to hip ratio (0.83). Both groups had similar SHBG (117 vs. 124 nmol/L) and free testosterone (3.7 vs. 3.4 pmol/L) levels, but AA women had a 35% higher leptin, 34% higher fasting insulin, and 39% greater insulin response to a glucose load (P < 0.05) compared with CAU women. In CAU, but not AA, women SHBG correlated negatively with body mass index (r = −0.28; P < 0.05), waist (r = −0.36; P = 0.01), IAF (r = −0.34; P = 0.01), and insulin response to oral glucose (r = −0.37; P < 0.05) and positively with high density lipoprotein cholesterol (r = 0.30; P = 0.03). The relationship between insulin area and SHBG in CAU women disappeared after adjusting for IAF, whereas the relationship between high density lipoprotein cholesterol and SHBG persisted after adjusting for IAF, but not for fat mass. Leptin was positively related to fat mass (P < 0.05) in both groups, but it was related to insulin only in the Caucasian women (P < 0.01). There was a racial difference in the slopes (P < 0.05) of the relationships of leptin to fat mass (P < 0.05). Racial differences in leptin disappeared after adjustment for fasting insulin. These results suggest that the metabolic relationships between total and regional obesity, glucose, and lipid metabolism with SHBG in CAU women are different from those in postmenopausal obese AA women.
Decreased Expression of Wnt7a mRNA Is Inversely Associated with the Expression of Estrogen Receptor-α in Human Uterine Leiomyoma
Authors: Li Shuanfang , Chiang Tung-Chin , Davis Gloria R. , Williams Rachele M. , Wilson Valerie P. , McLachlan John A.
Published: January 2014

Wnt-7a gene not only guides the development of the anterior-posterior axis in the female reproductive tract, but also plays a critical role in uterine smooth muscle pattering and maintenance of adult uterine function. This gene is also responsive to changes in the levels of sex steroid hormone in the female reproductive tract. To explore the molecular mechanisms underlying the pathogenesis of uterine leiomyoma, the expression of Wnt7a mRNA in the leiomyoma has been assessed. RT-PCR was performed on uterine leiomyomas and the adjacent myometria. Of 30 cases of leiomyomas studied, 67% showed a decreased mRNA level as compared to the paired myometria. On the other hand, estrogen receptor-α (ER-α) mRNA is hyper-expressed in 67% of the leiomyomas as compared to their paired myometrium. An inverse association at mRNA expression was found between Wnt7a and ER-α. Miller et alhas shown that fetal exposure of DES results in de-regulation of Wnt7a during uterine morphogenesis. Referring to their results, we have postulated that hypersensitivity of leiomyoma cells to estrogen may deregulate the Wnt7a expression. Decreased expression of Wnt7a may lead to loss of control in patterning of the myometrium and result in development of leiomyoma
A Novel Mutation of the Autoimmune Regulator Gene in an Italian Kindred with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, Acting in a Dominant Fashion and Strongly Cosegregating with Hypothyroid Autoimmune Thyroiditis
Authors: Cetani Filomena , Barbesino Giuseppe , Borsari Simona , Pardi Elena , Cianferotti Luisella , Pinchera Aldo , Marcocci Claudio
Published: January 2014

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is caused by mutations of the autoimmune regulator gene.

We identified an Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and a pattern of inheritance suggestive of a dominant mechanism. Serological and clinical studies showed a high prevalence of hypothyroid autoimmune thyroiditis in affected members with classical autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Direct sequencing of the entire coding region of the autoimmune regulator gene revealed the presence in the proband of a novel missense (G228W) mutation in exon 6 in a heterozygous state. The same heterozygous mutation was identified in all family members with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy and/or hypothyroid autoimmune thyroiditis. None of the unaffected family members and 50 unrelated Italian controls carried the mutation.

In contrast with all other autoimmune regulator mutations reported in families, the novel G228W mutation acts in a dominant fashion in our family, as only one heterozygous mutation was found in the entire coding sequence of the autoimmune regulator gene in the proband. Moreover, analysis of the family tree showed direct transmission of the hypothyroid autoimmune thyroiditis/polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype to the offspring in each generation in the absence of consanguinity, further supporting a dominant inheritance. The G228W closely cosegregated with hypothyroid autoimmune thyroiditis in our family, whereas a low penetrance of the full autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype was observed.

In conclusion, we report a novel mutation of the autoimmune regulator gene in a family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, closely cosegregating with hypothyroid autoimmune thyroiditis. The G228W mutation acts in a dominant fashion and may shed light on the structure-function relationship of the autoimmune regulator protein.
Glucose-Induced Insulin Hypersecretion in Lipid-Infused Healthy Subjects Is Associated with a Decrease in Plasma Norepinephrine Concentration and Urinary Excretion
Authors: Magnan Christophe , Cruciani Céline , Clément Laurence , Adnot Pierre , Vincent Mylène , Kergoat Micheline , Girard Arlette , Elghozi Jean-Luc , Velho Gilberto , Beressi Nathalie , Bresson Jean-Louis , Ktorza Alain
Published: January 2014

We investigated the effect of a 48 h triglyceride infusion on the subsequent insulin secretion in response to glucose in healthy men. We measured the variations in plasma concentration and urinary excretion of catecholamines as an indirect estimation of sympathetic tone. For 48 h, 20 volunteers received a triglyceride/heparin or a saline solution, separated by a 1-month interval. At time 48 h, insulin secretion in response to glucose was investigated by a single iv glucose injection (0.5 g/kg−1) followed by an hyperglycemic clamp (10 mg·kg−1·min−1, during 50 min). The triglyceride infusion resulted in a 3-fold elevation in plasma free fatty acids and an increase in insulin and C-peptide plasma concentrations (1.5- and 2.5-fold, respectively, P < 0.05), compared with saline. At time 48 h of lipid infusion, plasma norepinephrine (NE) concentration and urinary excretion levels were lowered compared with saline (plasma NE: 0.65 ± 0.08 vs. 0.42 ± 0.06 ng/ml, P < 0.05; urinary excretion: 800 ± 70 vs. 620 ± 25 nmol/24 h, P < 0.05). In response to glucose loading, insulin and C-peptide plasma concentrations were higher in lipid compared with saline infusion (plasma insulin: 600 ± 98 vs. 310 ± 45 pm, P < 0.05; plasma C-peptide 3.5 ± 0.2 vs. 1.7 ± 0.2 nm, P < 0.05). In conclusion, in healthy subjects, a 48-h lipid infusion induces basal hyperinsulinemia and exaggerated insulin secretion in response to glucose which may be partly related to a decrease in sympathetic tone.
Evidence for Genetic Factors Explaining the Association Between Birth Weight and Low-Density Lipoprotein Cholesterol and Possible Intrauterine Factors Influencing the Association Between Birth Weight and High-Density Lipoprotein Cholesterol: Analysis in Twins
Authors: IJzerman Richard G. , Stehouwer Coen D. A. , van Weissenbruch Mirjam M. , de Geus Eco J. , Boomsma Dorret I.
Published: January 2014

Recent studies have demonstrated an association between low weight at birth and an atherogenic lipid profile in later life. To examine the influences of intrauterine and genetic factors, we investigated 53 dizygotic and 61 monozygotic adolescent twin pairs. Regression analysis demonstrated that low birth weight was associated with high levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (−0.17 mmol/liter per kg, P = 0.07; −0.18 mmol/liter per kg, P = 0.04; and− 0.07 g/liter per kg, P = 0.02, respectively) and with low levels of high-density lipoprotein (HDL) cholesterol (+0.04 mmol/liter per kg, P = 0.1), after adjustment for age, sex, and body mass index. Intrapair differences in birth weight were significantly associated with differences in total cholesterol, LDL cholesterol, and apolipoprotein B in dizygotic twins after adjustment for differences in current body mass index (−0.49 mmol/liter per kg, P = 0.02; −0.51 mmol/liter per kg, P = 0.01; and −0.10 g/liter per kg, P = 0.04, respectively), demonstrating that the larger the difference in birth weight, the higher these risk factors in the twin with the lower birth weight, compared with the cotwin with the higher birth weight. In monozygotic twins, however, the associations between intrapair differences in birth weight and differences in total cholesterol, LDL cholesterol, and apolipoprotein B were in the opposite direction (+0.32 mmol/liter per kg, P = 0.03; +0.23 mmol/liter per kg, P = 0.08; and +0.06 g/liter per kg, P = 0.04, respectively). The association between intrapair differences in birth weight and differences in HDL cholesterol was not significant in dizygotic twins (+0.04 mmol/liter per kg, P = 0.6) and of borderline significance in monozygotic twins (+0.11 mmol/liter per kg, P = 0.05). These data suggest that genetic factors account for the association of low birth weight with high levels of total cholesterol, LDL cholesterol, and apolipoprotein B, whereas intrauterine factors possibly play a role in the association between birth weight and HDL cholesterol.
Oral Glucose Augments the Counterregulatory Hormone Response during Insulin-Induced Hypoglycemia in Humans1
Authors: Heptulla Rubina A. , Tamborlane William V. , Ma Tony Y.-Z. , Rife Fran , Sherwin. Robert S.
Published: January 2014

It has been suggested that the counterregulatory hormone (CRH) response to acute hypoglycemia is triggered via glucose sensors situated in either the hypothalamus or the portohepatic area. If the latter were critical during hypoglycemia, one would anticipate that ingestion of glucose, by raising glucose levels in the portal circulation, should attenuate CRH responses previously described in animal studies. To evaluate the effect of raising portal, but not peripheral, glucose levels during insulin-induced hypoglycemia, we performed hypoglycemic clamp studies in five healthy adult males on two occasions. On one occasion, subjects received oral glucose (OG) (25 g) during hypoglycemia; and on one occasion, noncarbohydrate-containing drink of equal volume, while maintaining plasma glucose at 55 ± 2 mg/dL (3.08 mmol/L).

As a result, there were no significant differences in systemic plasma glucose levels between the two hypoglycemic clamp studies, and basal CRH concentrations were also similar. As expected, there was a brisk rise in all CRH during the control (hypoglycemia+noncarbohydrate drink) study. In the experimental study, administration of OG (hypoglycemia+OG), to raise intraportal glucose levels during systemic hypoglycemia, did not attenuate CRH responses. Indeed, OG enhanced the rise in epinephrine, glucagon, and GH.

Increases in cortisol and norepinephrine did not differ between the two studies.

Therefore, our data suggest that increasing the level of glucose in the portal vein above that in the systemic circulation, during hypoglycemia, enhances (rather than suppresses) CRH responses. Thus, ingestion of glucose may reverse hypoglycemia directly by provision of substrate, as well as indirectly by stimulating counteregulatory mechanisms.
The Impact of Irradiation on Growth Hormone Responsiveness to Provocative Agents Is Stimulus Dependent: Results in 161 Individuals with Radiation Damage to the Somatotropic Axis1
Authors: Lissett C. A. , Saleem S. , Rahim A. , Brennan B. M. D. , Shalet S. M.
Published: January 2014

GH provocative tests remain the mainstay for the diagnosis of GH deficiency and at present the insulin tolerance test (ITT) is the gold standard. There are, however, a variety of other stimulation tests used in clinical practice. Each necessitates the use of a specific cut-off derived from normative data, but there remains a widely held view that the implications from a “failed” test are independent of the nature of the stimulus. We sought to examine whether this is the case in individuals with evidence of radiation damage to the somatotropic axis.

One hundred and sixty-one nonacromegalic patients were identified who had undergone an arginine stimulation test (AST) and an ITT within a 3-month period as part of routine testing between 1975 and 1999. They were divided into those tested before (n = 81; 48 males) and those tested after (n = 80; 36 males) completion of growth and puberty. Patients were considered for inclusion in the study if they had a history of cranial irradiation and a GH response to one provocative test of less than 8 μg/L, taken as indicating that some damage to the GH axis may have occurred. The patients were compared with 2 control groups. The first comprised 35 adults (18 males) and the second consisted of 16 prepubertal children (10 males).

The median peak (range) GH response to the ITT was significantly greater (P < 0.0001) than that to the AST in the adult controls: 24.9 (4.1–76.9) vs. 12.2 (0.88–35.0)μ g/L, respectively. However, in the patients the GH responses were similar (P = 0.28): 2.2 (0.2–25.7) vs. 1.4 (0.2–12.8) μg/L to the ITT and AST, respectively. In contrast to the pattern seen in the adult controls, the response to an ITT in childhood controls was of similar magnitude (P = 0.5) to that to the AST: 17.5 (8.1–40.0) vs. 19.4 (7.3–53.8) μg/L, respectively. However in the patients, the GH response to the AST was greater than that to the ITT (P < 0.0001): 4.3 (0.7–17.2) vs. 3.0 (0.4–18.1) μg/L, respectively.

In summary, we have shown that the impact of irradiation on GH responsiveness to provocative agents is stimulus dependent. The GH response to an AST appears to be more resistant to the effects of irradiation than that to the ITT. When investigating the impact of irradiation on GH secretory status, the GH response to an AST may be a less sensitive guide to the functional ability of the GH axis.