bluuebunny/crossref_metadata_2025_split huggingface dataset:
Failure of Cortisone Acetate Treatment in Congenital Adrenal Hyperplasia because of Defective 11β-Hydroxysteroid Dehydrogenase Reductase Activity*
Authors: Nordenström Anna , Marcus Claude , Axelson Magnus , Wedell Anna , Ritzén E. Martin 
Published: January 2014

Congenital adrenal hyperplasia in children is often treated with cortisone acetate and fludrocortisone. It is known that certain patients with congenital adrenal hyperplasia require very high substitution doses of cortisone acetate, and a few patients do not respond to this treatment at all.A patient with 21-hydroxylase deficiency, for whom elevated pregnanetriol (P3) levels in urine were not suppressed during treatment with cortisone acetate (65 mg/m2·day), was examined. The activation of cortisone to cortisol was assessed by measuring urinary metabolites of cortisone and cortisol.The patient’s inability to respond to treatment with cortisone acetate was found to be caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11β-hydroxysteroid dehydrogenase activity (11-oxoreductase deficiency). All exons and exon/intron junctions of the 11β-hydroxysteroid dehydrogenase type1 gene (HSD11L) were sequenced without finding any mutations, but a genetic lesion in the promoter or other regulatory regions cannot be ruled out. The deficient 11-oxoreductase activity seems to have been congenital, in this case, but can possibly be attributable to a down-regulation of the enzyme activity. The results support the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.
Angiogenesis in Pituitary Adenomas and the Normal Pituitary Gland
Authors: Turner Helen E. , Nagy Zsusha , Gatter Kevin C. , Esiri Margaret M. , Harris Adrian L. , Wass John A. H. 
Published: January 2014

Abstract
Angiogenesis is essential for tumor growth beyond a few millimeters in diameter, and the intratumoral microvessel count that represents a measure of angiogenesis has been correlated with tumor behavior in a variety of different tumor types. To date no systematic study has assessed pituitary tumors of different secretory types, correlating vascular count with tumor size. The vascular densities of pituitary tumors and normal anterior pituitary were therefore assessed by counting vessels labeled using the vascular markers CD31 and ulex europaeus agglutinin I. One hundred and twelve surgically removed pituitary adenomas (30 GH-secreting, 25 prolactinomas, 15 ACTH-secreting, and 42 nonfunctioning tumors) were compared with 13 specimens of normal anterior pituitary gland. The vascular counts in the normal anterior pituitary gland were significantly higher (P &lt; 0.05) than those in the tumors using both CD31 and ulex europaeus agglutinin I. In addition, microprolactinomas were significantly less vascular (P &lt; 0.05) than macroprolactinomas, although there was no such difference between vascular densities of microadenomas and macroadenomas producing GH. ACTH-secreting tumors were, like microprolactinomas, of much lower vascular density than the normal pituitary and other secreting and nonsecreting tumor types. In marked contrast to other tumors, pituitary adenomas are less vascular than the normal pituitary gland, suggesting that there may be inhibitors of angiogenesis that play an important role in the behavior of these tumors.
Familial Hypercalcemia and Hypercalciuria Caused by a Novel Mutation in the Cytoplasmic Tail of the Calcium Receptor*
Authors: Carling Tobias , Szabo Eva , Bai Mei , Ridefelt Peter , Westin Gunnar , Gustavsson Peter , Trivedi Sunita , Hellman Per , Brown Edward M. , Dahl Niklas , Rastad Jonas 
Published: January 2014

Abstract
Familial hyperparathyroidism (HPT), characterized by hypercalcemia and hypercalciuria, and familial benign hypocalciuric hypercalcemia (FHH) are the most common causes of hereditary hypercalcemia. The calcium-sensing receptor (CaR) regulates PTH secretion and renal calcium excretion. Heterozygous inactivating mutations of the gene cause FHH, whereas CaR gene mutations have not been demonstrated in HPT. In a kindred with 20 affected individuals, the hypercalcemic disorder segregated with inappropriately higher serum PTH and magnesium levels and urinary calcium levels than in unaffected members. Subtotal parathyroidectomy revealed parathyroid gland hyperplasia/adenoma and corrected the biochemical signs of the disorder in seven of nine individuals. Linkage analysis mapped the condition to markers flanking the CaR gene on chromosome 3q. Sequence analysis revealed a mutation changing phenylalanine to leucine at codon 881 of the CaR gene, representing the first identified point mutation located within the cytoplasmic tail of the CaR. A construct of the mutant receptor (F881L) was expressed in human embryonic kidney cells (HEK 293), and demonstrated a right-shifted dose-response relationship between the extracellular and intracellular calcium concentrations. The hypercalcemic disorder of the present family is caused by an inactivating point mutation in the cytoplasmic tail of the CaR and displays clinical characteristics atypical of FHH and primary HPT.
Variations in Vitamin D-Binding Protein (Group-Specific Component Protein) Are Associated with Fasting Plasma Insulin Levels in Japanese with Normal Glucose Tolerance*
Authors: Hirai Masashi , Suzuki Susumu , Hinokio Yoshinori , Hirai Aki , Chiba Masaki , Akai Hiroaki , Suzuki Chitose , Toyota Takayoshi 
Published: January 2014

Abstract
The locus of the vitamin D-binding protein (DBP; also known as group-specific component protein or Gc) gene, chromosome 4q12, has been reported to be associated with glucose metabolism in several ethnic groups, including Pima Indians. We have recently reported the association of the DBP genotype with type 2 diabetes mellitus in Japan. The aim of this study was to investigate whether genetic variations of DBP have any influence on glucose metabolism without secondary effects of hyperglycemia or diabetes mellitus using 82 Japanese with normal glucose tolerance. The variations of the DBP gene (Gc 1F, 1S, and 2) were determined by PCR-restriction fragment length polymorphism. Fasting plasma insulin concentration and homeostasis model assessment, an index of insulin resistance, were significantly different based on the DBP genotype (P &lt; 0.01 and P &lt; 0.05, respectively). The people with Gc 1S-2 (5.73 ± 2.57 μU/mL) and 1S-1S (5.30 ± 3.46 μU/mL) had significantly higher fasting plasma concentrations than those with 1F-1F (2.84 ± 1.67 μU/mL) (P &lt; 0.01 and P &lt; 0.03, respectively). There was no significant difference in plasma glucose concentration, body mass index, total cholesterol, triglyceride, and blood pressure. In conclusion, genetic variations of DBP are associated with insulin resistance in Japanese with normal glucose tolerance, which might contribute to the development of type 2 diabetes.
Pediatric Adrenocortical Tumors: Molecular Events Leading to Insulin-Like Growth Factor II Gene Overexpression*
Authors: Wilkin Françoise , Gagné Nancy , Paquette Jean , Oligny Luc L. , Deal Cheri 
Published: January 2014

AbstractIt has been previously shown that adrenocortical tumors (ACT) in adults exhibit structural abnormalities in tumor DNA in approximately 30% of cases. These abnormalities involve chromosome 11p15 and include loss of heterozygosity, paternal isodisomy, and overexpression of the gene for insulin-like growth factor II (IGF2), correlating with DNA demethylation at this locus. It has been hypothesized that these events occur late in the tumorigenic process in adults and seem to correlate with a worse prognosis. We present 4 pediatric cases of ACT diagnosed at 2.5 yr, 10 months, 12 yr, and 2.2 yr. All 4 patients presented with virilization, and 1 patient also showed signs and symptoms of glucocorticoid excess. The youngest patient’s maternal aunt had surgical excision of a more than 15-cm ACT 18 yr previously, but the aunt is doing well at age 23 yr. They all had surgical removal of their tumors. The 2.5-yr-old child also received chemotherapy and radiotherapy because of capsular rupture and, after 3 local recurrences, died 3.3 yr after initial presentation. We investigated all 4 tumors for chromosome 11 structural abnormalities (11p15.5 to 11q23), IGF2 and H19 expression by competitive RT-PCR analysis, and IGF2 methylation patterns by Southern analysis. All 4 tumors (100%) showed a combination of structural abnormalities at the 11p15 locus with mosaic loss of heterozygosity involving 11p. All tumors also had significantly increased IGF2 messenger ribonucleic acid levels relative to normal adrenal (up to 36-fold) and significant IGF2 demethylation (mean, 87%). H19 messenger ribonucleic acid levels were undetectable in 3 of 4 tumors, explained in part by mosaic loss of the actively expressed maternal allele for this imprinted gene. By immunohistochemistry we were able to confirm increased IGF-II peptide levels within the tumor tissue in 10 pediatric patients, including the 4 patients described above. Concomitantly, we also observed nuclear accumulation of p53, suggesting somatic mutations. For the 10-month-old patient, sequencing revealed a p53 germline mutation. We therefore conclude that in pediatric ACT, structural abnormalities of tumor DNA and IGF2 overexpression as well as p53 mutations are very common and are therefore less useful for prognosis than in adults. Our findings support the theory that pediatric ACT, whose IGF2 expression and steroidogenesis evoke the phenotype of the fetal adrenal cortex, may arise because of defective apoptosis.
Recombinant Human Insulin-Like Growth Factor I Has Significant Anabolic Effects in Adults with Growth Hormone Receptor Deficiency: Studies on Protein, Glucose, and Lipid Metabolism*
Authors: Mauras Nelly , Martinez Victor , Rini Annie , Guevara-Aguirre Jaime 
Published: January 2014

Abstract
The physiological effects of insulin-like growth factor I (IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron’s syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean ± sem age, 29.2 ± 2.0 yr; 4 males and 6 females). At baseline, patients had infusions of stable tracers, including l-[13C]leucine,[ 2H2]glucose, and d5-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60μ g/kg, sc) for the next 8 weeks when the studies were repeated identically.
Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 ± 1.5 μg/L to 153 ± 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods (P &lt; 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid andβ -hydroxybutyrate concentrations, and a significant increase in fat oxidation, as measured by indirect calorimetry (P = 0.04). There were significant decreases in insulin concentrations (P = 0.01) and a reciprocal increase in glucose production rates (P = 0.04) during rhIGF-I, yet plasma glucose concentrations remained constant, suggestive of a significant insulin-like action of this peptide. RhIGF-I was well tolerated by all patients.
In conclusion, 8 weeks of treatment with rhIGF-I had significant positive effects on body composition and measures of intermediate metabolism independent of GH. These results suggest that, similar to GH treatment of adults with GH deficiency, rhIGF-I may be beneficial as long term replacement therapy for the adult patient with Laron’s syndrome.
Anabolic-Androgenic Steroid Therapy in the Treatment of Chronic Diseases
Authors: Basaria Shehzad , Wahlstrom Justin T. , Dobs Adrian S. 
Published: January 2014

The purpose of this study was to review the preclinical and clinical literature relevant to the efficacy and safety of anabolic androgen steroid therapy for palliative treatment of severe weight loss associated with chronic diseases. Data sources were published literature identified from the Medline database from January 1966 to December 2000, bibliographic references, and textbooks. Reports from preclinical and clinical trials were selected. Study designs and results were extracted from trial reports. Statistical evaluation or meta-analysis of combined results was not attempted.Androgenic anabolic steroids (AAS) are widely prescribed for the treatment of male hypogonadism; however, they may play a significant role in the treatment of other conditions as well, such as cachexia associated with human immunodeficiency virus, cancer, burns, renal and hepatic failure, and anemia associated with leukemia or kidney failure. A review of the anabolic effects of androgens and their efficacy in the treatment of these conditions is provided. In addition, the numerous and sometimes serious side effects that have been known to occur with androgen use are reviewed.Although the threat of various side effects is present, AAS therapy appears to have a favorable anabolic effect on patients with chronic diseases and muscle catabolism. We recommend that AAS can be used for the treatment of patients with acquired immunodeficiency syndrome wasting and in severely catabolic patients with severe burns. Preliminary data in renal failure-associated wasting are also positive. Advantages and disadvantages should be weighed carefully when comparing AAS therapy to other weight-gaining measures. Although a conservative approach to the use of AAS in patients with chronic diseases is still recommended, the utility of AAS therapy in the attenuation of severe weight loss associated with disease states such as cancer, postoperative recovery, and wasting due to pulmonary and hepatic disease should be more thoroughly investigated.
Growth Hormone (GH) Secretion in Patients with an Inactivating Defect of the GH-Releasing Hormone (GHRH) Receptor Is Pulsatile: Evidence for a Role for Non-GHRH Inputs into the Generation of GH Pulses
Authors: Roelfsema Ferdinand , Biermasz Nienke R. , Veldman Ronald Groote , Veldhuis Johannes D. , Frölich Marijke , Stokvis-Brantsma W. Henriëtte , Wit Jan-Maarten 
Published: January 2014

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10–20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26–63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96–390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P &lt; 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 μg GHRH failed to increase the plasma GH concentration in both patients, but 100 μg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning.
In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.
TNF-α and Hyperandrogenism: A Clinical, Biochemical, and Molecular Genetic Study
Authors: Escobar-Morreale Héctor F. , Calvo Rosa M. , Sancho José , San Millán José L. 
Published: January 2014

To evaluate the role of TNF-α in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-α levels, as well as several polymorphisms in the promoter region of the TNF-α gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index.
Hyperandrogenic patients presented with mildly increased serum TNF-α levels as compared with controls (mean[median] ± sd: 7.2[7.0] ± 3.3 pg/ml vs. 5.6[4.4] ± 4.0 pg/ml, P &lt; 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-α was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls.
The TNF-α gene polymorphisms studied here (−1196C/T, −1125G/C,− 1031T/C, −863C/A, −857C/T, −316G/A, −308G/A, −238G/A, and− 163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the −308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-α levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants.
In conclusion, our present results suggest that the TNF-α system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-α system and androgen excess is needed before considering TNF-α as a significant contributing factor to the development of hyperandrogenism.
The −597 G→A and −174 G→C Polymorphisms in the Promoter of the IL-6 Gene Are Associated with Hyperandrogenism
Authors: Villuendas Gemma , San Millán José L. , Sancho José , Escobar-Morreale Héctor F. 
Published: January 2014

To evaluate whether genetic variability at the IL-6 gene (IL-6) is associated with hyperandrogenism, we studied four common polymorphisms in the IL-6 promoter (−597G→A, −572G→C, −373AnTn, −174G→C) in 85 hyperandrogenic patients and 25 healthy women. We found 5 different haplotypes when considering the 3 biallelic polymorphisms at positions −597, −572, and −174 of IL-6 (relative frequencies in parentheses): GGG (0.505), AGC (0.377), GGC (0.059), GCG (0.055), and GCC (0.005). The frequencies of the GGG haplotype were 0.559 in patients and 0.320 in controls, whereas those of the AGC haplotype were 0.318 in patients and 0.580 in controls (χ2 = 12.145; P &lt; 0.02). The −597G→A and −174G→C polymorphisms were in linkage disequilibrium (χ2 = 152.220; P &lt; 0.00001), and were associated with patient or control status. −597G and −174G alleles were more frequent in patients in homozygosity or considering subjects homozygous and heterozygous for G alleles as a whole (P &lt; 0.05 for all analyses).
In healthy women G alleles at −597 and −174 were associated with statistically significant higher circulating levels of IL-6 and basal cortisol, 11-deoxycortisol, and 17-hydroxyprogesterone and a tendency (P &lt; 0.10) for higher total T concentrations compared with −597A and −174C alleles. On the contrary, neither the −572G→C nor the −373AnTn polymorphism was related to hyperandrogenism or influenced any clinical or biochemical variable.
In conclusion, our present results suggest that the −597G→A and −174G→C polymorphisms in IL-6 are involved in the pathogenesis of hyperandrogenic disorders.
Analysis of the Role of E2A-Encoded Proteins in Insulin Gene Transcription
Authors: Sharma Arun , Henderson Eva , Gamer Laura , Zhuang Yuan , Stein Roland 
Published: January 2014

AbstractPancreatic β-cell type-specific transcription of the insulin gene is mediated, in part, by factors in the basic helix-loop-helix (bHLH) family that act on a site within the insulin enhancer, termed the E1-box. Expression from this element is regulated by a heteromeric protein complex containing ubiquitous (i.e. the E2A- and HEB-encoded proteins) and islet-enriched members of the bHLH family. Recent studies indicate that the E2A- and HEB-encoded proteins contain a transactivation domain, termed AD2, that functions more efficiently in transfected β-cell lines. In the present report, we extend this observation by demonstrating that expression of full-length E2A proteins (E47, E12, and E2/5) activates insulin E element-directed transcription in a β-cell line-selective manner. Stimulation required functional interactions with other key insulin gene transcription factors, including its islet bHLH partner as well as those that act on the RIPE3b1 and RIPE3a2 elements of the insulin gene enhancer. The conserved AD2 domain in the E2A proteins was essential in this process. The effect of the E2A- and HEB-encoded proteins on insulin gene expression was also analyzed in mice lacking a functional E2A or HEB gene. There was no apparent difference in insulin production between wild type, heterozygote, and homozygous mutant E2A or HEB mice. These results suggest that neither the E2A- or HEB-encoded proteins are essential for insulin transcription and that one factor can substitute for the other to impart normal insulin E1 activator function in mutant animals.