bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotype: Genotype Relationships in Growth Hormone Insensitivity Syndrome1
Authors: Woods Katie A. , Dastot Florence , Preece Michael A. , Clark Adrian J. L. , Postel-Vinay Marie-Catherine , Chatelain Pierre G. , Ranke Michael B. , Rosenfeld Ron G. , Amselem Serge , Savage Martin O. 
Published: January 2014

GH insensitivity syndrome (GHIS) is associated with many different mutations of the GH receptor (GHR) gene. We examined the phenotypic and biochemical features in 82 GHIS patients from 23 countries, each fulfilling diagnostic criteria of GHIS. There were 45 males and 37 females [mean age, 8.25 yr; mean height, −6.09 sd score, and mean insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3),− 7.99 sd score]. Sixty-three were GH-binding protein (GHBP) negative; 19 were GHBP positive (&gt;10% binding). The mean height in GHBP-negative subjects was −6.5 sd score, and that in GHBP-positive patients was −4.9 sd score (P = &lt;0.001). Clinical and biochemical heterogeneity was demonstrated by the wide range of height (−2.2 to− 10.4 sd score) and IGFBP-3 (−1.4 to −14.7 sd score) values, which were positively correlated (r2 = 0.45; P = &lt;0.001). This contrasted with the lack of correlation between mean parental height sd score and height sd score (r2 = 0.01).
Fifteen different GH receptor gene mutations were identified in 27 patients. All had homozygous defects, except 1 who had a compound heterozygous defect. The mutations were 5 nonsense, 2 frame shift, 4 splice, 4 missense, and 1 compound heterozygote. There was no relationship between mutation type or exon of the GHR gene involved and height or IGFBP-3 sd score.
In conclusion, GHIS is associated with wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene. Other genetic and/or environmental factors must, therefore, contribute to phenotype in GHIS.
Diabetes during Pregnancy Does Not Alter Whole Body Bone Mineral Content in Infants
Authors: Lapillonne Alexandre , Guerin Sophie , Braillon Pierre , Claris Olivier , Delmas Pierre D. , Salle Bernard L. 
Published: January 2014

A previous study using single photon absorptiometry has reported low bone mineral density of the radius in infants of diabetic mothers. The aim of this study was to assess by dual x-ray absorptiometry the whole body bone mineral content (WbBMC) and the body composition of 40 infants of diabetic mothers at birth (mean gestational age ± sd, 37.5 ± 1.3 weeks; mean birth weight ± sd, 3815 ± 641 g).WbBMC was not correlated with gestational age, but was well correlated with birth weight (r = 0.73; P = 0.0001) and also with fat mass (r = 0.87; P = 0.0001) and lean mass (r = 0.42; P = 0.008). The z-scores ± sd adjusted for weight for WbBMC and fat mass were significantly increased (1.3 ± 0.9 and 2.6 ± 1.3, respectively (P &lt; 0.0001), but were not significantly influenced either by in utero growth or by the type of the diabetes mellitus of the mother.Bone mineralization and fat mass studied by whole body dual x-ray absorptiometry are increased at birth in these infants compared with reference curves.
Clinical, Biochemical, and Molecular Investigations of a Genetic Isolate of Growth Hormone Insensitivity (Laron’s Syndrome)*
Authors: Baumbach L. , Schiavi A. , Bartlett R. , Perera E. , Day J. , Brown M. R. , Stein S. , Eidson M. , Parks J. S. , Cleveland W. 
Published: January 2014

Abstract
We have characterized the GH receptor mutation that is responsible for extreme short stature and GH insensitivity in a Bahamian genetic isolate. Heights of affected individuals ranged from −4.0 to −6.3 sd. Like others with Laron’s syndrome, they had normal to high serum GH concentrations and low serum insulin-like growth factor I concentrations. Circulating levels of GH-binding protein activity were below limits of detection. Amplification of exons 2–7 and screening with single strand conformational polymorphism analysis located an abnormality in exon 7. Sequencing identified homozygosity for a C to T transition in the third position of codon 236. Reverse transcription and PCR amplification of complementary DNA from lymphocytes showed that this same sense mutation generated a new splice donor site 63 bp 5′ to the normal exon 7 splice site. This novel site was used to the exclusion of the normal site in homozygotes. Both normal and variant messenger ribonucleic acid species were detected in heterozygotes. The predicted protein lacks 21 amino acids, including those defining the WS-like motif of the GH receptor extracellular domain. The high frequency of Laron’s syndrome in this isolated island population probably reflects the introduction of the G236 splice mutation by a settler early in the 300-yr history of English settlement.
Estimation of Tissue Hypothyroidism by a New Clinical Score: Evaluation of Patients with Various Grades of Hypothyroidism and Controls1
Authors: Zulewski Henryk , Müller Beat , Exer Pascale , Miserez André R. , Staub Jean-Jacques 
Published: January 2014

Abstract
The classical signs and symptoms of hypothyroidism were reevaluated in the light of the modern laboratory tests for thyroid function. We analyzed 332 female subjects: 50 overt hypothyroid patients, 93 with subclinical hypothyroidism (SCH), 67 hypothyroid patients treated with T4, and 189 euthyroid subjects. The clinical score was defined as the sum of the 2 best discriminating signs and symptoms. Beside TSH and thyroid hormones, we measured parameters known to reflect tissue manifestations of hypothyroidism, such as ankle reflex relaxation time and total cholesterol.
Classical signs of hypothyroidism were present only in patients with severe overt hypothyroidism with low T3, but were rare or absent in patients with normal T3 but low free T4 or in patients with SCH (normal thyroid hormones but elevated basal TSH; mean scores, 7.8 ± 2.7 vs. 4.4 ± 2.2 vs. 3.4 ± 2.0; P &lt; 0.001). Assessment of euthyroid subjects and T4-treated patients revealed very similar results (mean score, 1.6 ± 1.6 vs. 2.1 ± 1.5). In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P &lt; 0.0001), but no correlation with TSH (r = 0.01). The correlation with free T4 was r = −0.52 (P &lt; 0.0004), and that with T3 was r = −0.56 (P &lt; 0.0001). In SCH, the best correlation was found between the new score and free T4 (r =− 0.41; P &lt; 0.0001) and TSH (r = 0.35; P &lt; 0.0005).
Evaluation of symptoms and signs of hypothyroidism with the new score in addition to thyroid function testing is very useful for the individual assessment of thyroid failure and the monitoring of treatment.
I. Adrenal Cortex and Steroid 21-Hydroxylase Autoantibodies in Adult Patients with Organ-Specific Autoimmune Diseases: Markers of Low Progression to Clinical Addison’s Disease
Authors: Betterle Corrado , Volpato Marina , Smith Bernard Rees , Furmaniak Jadwiga , Chen Shu , Greggio Nella A. , Sanzari Maria , Tedesco Francesco , Pedini Beniamino , Boscaro Marco , Presotto Fabio 
Published: January 2014

Abstract
Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylase (21-OH), steroid 17α-hydroxylase (17α-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17α-OH and/or P450scc. During the prospective study, overt Addison’s disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison’s disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17α-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison’s disease. .
The Metabolic Significance of Leptin in Humans: Gender-Based Differences in Relationship to Adiposity, Insulin Sensitivity, and Energy Expenditure*
Authors: Kennedy Adele , Gettys Thomas W. , Watson Patricia , Wallace Penny , Ganaway Elizabeth , Pan Qin , Garvey W. Timothy 
Published: January 2014

Abstract
Leptin is an adipocyte-derived hormone that interacts with a putative receptor(s) in the hypothalamus to regulate body weight. The relationship of leptin to metabolic abnormalities associated with obesity together with hormonal and substrate regulation of leptin have not been extensively studied. Therefore, 116 subjects (62 men and 54 women) with a wide range of body weight [body mass index (BMI), 17–54 kg/m2] were characterized on a metabolic ward with regard to body composition, glucose intolerance, insulin sensitivity, energy expenditure, substrate utilization, and blood pressure. Eighty-five of the subjects had normal glucose tolerance (50 men and 35 women), and 31 had noninsulin-dependent diabetes mellitus (12 men and 19 women). In both men and women, fasting leptin levels were highly correlated with BMI (r = 0.87 and r = 0.88, respectively) and percent body fat (r = 0.82 and r = 0.88, respectively; all P &lt; 0.0001). However, men exhibited lower leptin levels at any given measure of obesity. Compared with those in men, leptin levels rose 3.4-fold more rapidly as a function of BMI in women[ leptin = 1.815 (BMI) − 31.103 in women; leptin = 0.534 (BMI) − 8.437 in men] and 3.2 times more rapidly as a function of body fat [leptin = 1.293 (% body fat) − 24.817 in women; leptin = 0.402 (% body fat) − 3.087 in men]. Hyperleptinemia was associated with insulin resistance (r = −0.57; P &lt; 0.0001) and high waist to hip ratio (r = 0.75; P &lt; 0.0001) only in men. On the other hand, during the hyperinsulinemic euglycemic clamp studies, hyperinsulinemia acutely increased leptin concentrations (20%) only in women. There was no correlation noted between fasting leptin levels and either resting energy expenditure or insulin-induced thermogenesis in men or women (P = NS). In stepwise and multiple regression models with leptin as the dependent variable, noninsulin-dependent diabetes mellitus did not enter the equations at a statistically significant level.
The data indicate that there are important gender-based differences in the regulation and action of leptin in humans. Serum leptin levels increase with progressive obesity in both men and women. However, for any given measure of obesity, leptin levels are higher in women than in men, consistent with a state of relative leptin resistance. These findings have important implications regarding differences in body composition in men and women. The observation that serum leptin is not related to energy expenditure rates suggests that leptin regulates body fat predominantly by altering eating behavior rather than calorigenesis.
Dual Hormonal Replacement Therapy with Insulin and Recombinant Human Insulin-Like Growth Factor (IGF)-I in Insulin-Dependent Diabetes Mellitus: Effects on the Growth Hormone/IGF/IGF-Binding Protein System*
Authors: Thrailkill Kathryn , Quattrin Teresa , Baker Lester , Litton Jean , Dwigun Karen , Rearson Melissa , Poppenheimer Mary , Kotlovker Debbie , Giltinan David , Gesundheit Neil , Martha Paul 
Published: January 2014

Abstract
Patients with insulin-dependent diabetes mellitus (IDDM) exhibit abnormalities in the GH/insulin-like growth factor (IGF) axis, including GH hypersecretion, low serum IGF-I and IGF-binding protein-3 (IGFBP-3) levels, and elevated IGFBP-1 levels. We recently demonstrated that in IDDM, dual hormonal replacement therapy with insulin plus recombinant human IGF-I (rhIGF-I) improves glycemic control better than insulin alone. To determine whether the addition of rhIGF-I therapy to insulin therapy also corrects GH/IGF/IGFBP abnormalities, we examined the effects of chronic combined rhIGF-I/insulin therapy on key components of the somatotropin axis. Forty-three pediatric IDDM patients were randomly assigned to groups receiving daily, fasting subcutaneous injections of placebo or rhIGF-I (80 μg•kg•day) for 28 days, while continuing to receive split-mix insulin therapy and intensive outpatient management. rhIGF-I therapy corrected IGF-I deficiency, suppressed IGFBP-1 levels (P &lt; 0.01), and induced a trend toward lower circulating GH levels throughout the study. rhIGF-I therapy also induced an approximate 50% decrease in IGF-II levels (P &lt; 0.001) and an approximate 70% increase in IGFBP-2 levels (P &lt; 0.05). Serum IGFBP-3 levels, normal before treatment, remained normal during rhIGF-I administration. All effects were apparent during the first week of rhIGF-I therapy and persisted throughout treatment. Because improvements in the GH/IGF axis abnormalities and in glycemic control were greater in subjects receiving combined rhIGF-I and insulin, these data strongly support the concept that dual hormonal replacement in IDDM may offer distinct therapeutic advantages over insulin monotherapy.
Short-Term Effects of Growth Hormone and Insulin-Like Growth Factor I on Cancellous Bone in Rhesus Macaque Monkeys*
Authors: Sass D. A. , Jerome C. P. , Bowman A. R. , Bennett-Cain A. , Ginn T. A. , LeRoith D. , Epstein S. 
Published: January 2014

AbstractThe purpose of our study was to determine the effects of GH and insulin-like growth factor I (IGF-I) administration singly and in combination on vertebral, tibial, and femoral bone in aged female monkeys as well as the various treatment effects on serum hormone levels and osteocalcin gene expression. Twenty-one ovulating female monkeys (rhesus macaque), aged 16–20 yr (5–6 kg), were divided into four groups to receive the following treatment for 7 weeks via Alzet pumps inserted sc: A, eluant (control group); B, recombinant human IGF-I (rhIGF-I; 120 μg/kg·day); C) rhGH (100 μg/kg·day); D, combination of rhIGF-I (120 μg/kg·day) and rhGH (100μ g/kg·day). Serum was assayed serially for glucose, IGF-I, GH, and IGF-binding protein-3 levels. All groups received double labeling with calcein. On the day of death, the primates’ second lumbar vertebrae, tibiae, and femora were carefully dissected, fixed in 70% ethanol, and subjected to histomorphometric analysis. Ribonucleic acid was extracted from contralateral tibiae for the purpose of osteocalcin gene expression analysis. Serum glucose was unaffected by treatment. Serum GH was significantly elevated in groups C and D, whereas serum IGF-I and IGFBP-3 were only significantly increased in group D. Histomorphometric analysis showed no significant differences or trends for bone volume in any treatment group. Bone formation rate, surface and/or bone volume referent were significantly higher in both groups treated with GH (C and D) in tibia and femur, with a similar trend in vertebrae. The increase in bone formation rate was due mainly to a significant increase in mineral apposition rate, but there was also an increase in tibial mineralizing surface by GH by factorial analysis (P &lt; 0.05). There were significant treatment effects on osteoid surface and osteoclastic surface in femur in the combination treatment group vs. the controls. Osteocalcin gene expression analysis supported an enhanced expression in both groups treated with GH. These findings are consistent with a short term effect of GH to increase bone remodeling and predominantly osteoblastic activity in the appendicular skeleton. In contrast, other than an isolated increase in osteoclastic surface in femoral bone, IGF-I, when administered alone, was unable to significantly influence bone formation or resorption activity in this short term study.
An Autosomal Dominant Form of Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy, Not Linked to the Sulfonylurea Receptor Locus*
Authors: Kukuvitis Asterios , Deal Cheri , Arbour Laura , Polychronakos Constantin 
Published: January 2014

AbstractPersistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare disorder due to defective negative feedback regulation of insulin secretion by low glucose levels, is often familial. Most cases are recessively inherited, and mutations of the sulfonylurea receptor gene (SUR) or the closely linked KIR6.2 gene have been found in several families. Both of these genes encode components of the potassium channels responsible for glucose-regulated insulin release. However, in some families recessive PHHI is not linked to the SUR-KIR6.2 locus, suggesting genetic heterogeneity. We report here a French Canadian kindred with hypoglycemia in five first cousins. All five patients had documented hypoglycemia, and all responded well to diazoxide. In two, inappropriately elevated insulin levels during hypoglycemia were documented. This familial clustering strongly suggests the existence of an autosomal dominant form of PHHI. By preliminary linkage analysis, we tested the possibility of a dominant negative SUR or KIR6.2 mutant. The insulin (INS) and glucokinase (GCK) genes were also tested as additional candidates. Microsatellite markers closely linked to each gene were used, and large negative Lod scores were obtained at the known recombination fractions between all three genes studied and the corresponding marker. We conclude that mutation of a gene other than SUR or KIR6.2 is responsible for the dominant PHHI in this family, and this gene cannot be INS or GCK. We propose that a genome-wide search for this gene is important for elucidating this rare disorder and, more importantly, for determining its potential impact on understanding noninsulin-dependent diabetes mellitus and on the effort to develop bioengineered β-cells for transplantation.
Expression of the Apoptosis-Suppressing Gene BCL-2 in Pheochromocytoma is Associated with the Expression of C-MYC
Authors: Wang Da-Gong , Johnston Colin F. , Marley John J. , Phenix Kerry V. , Atkinson A. Brew , Russell Colin F. J. , Buchanan Keith D. 
Published: January 2014

Abstract
It has become increasingly clear that deregulation of programmed cell death is a critical component in multistep tumorigenesis. Previous studies have demonstrated a high frequency of Bcl-2 expression in tumors arising from cells derived from the neural crest and in tumor cell lines of neural origin. The present investigation was undertaken to determine whether similar molecular events occur in human pheochromocytoma. With the aim of determining the potential role of apoptosis in the pathogenesis of this tumor, we assessed proto-oncogene Bcl-2 and c-myc protein products as well as Bcl-2 messenger RNA levels in a collection of such tumors. Western blot analysis revealed that such tumors expressed the 26 kDa Bcl-2 (5 of 8 cases) and the 64 kDa c-Myc (7 of 8 cases) proteins. Northern blot analysis detected the Bcl-2 transcripts in 6 of 8 tumors. Immunoperoxidase staining, using a monoclonal anti-Bcl-2 antibody, was positive in 18 (82%), including 5 malignant tumors, of the 22 specimens examined. This Bcl-2 immunoreactivity was seen in 14 of 18 (78%) sporadic tumors, including 2 that were extra-adrenal, and all familial tumors. Of the 22 tumor samples examined for c-Myc protein, 20 (91%) tumors were positive. Our results suggest that deregulation of programmed cell death may be a critical component in the multistep tumorigenesis of human pheochromocytoma. The genetic complementation of simultaneously deregulated Bcl-2 and c-myc may be implicated in this process.
Vitamin D Receptor Polymorphisms Correlate to Parathyroid Cell Function in Primary Hyperparathyroidism1
Authors: Carling Tobias , Ridefelt Peter , Hellman Per , Rastad Jonas , Åkerström Göran 
Published: January 2014

AbstractCalcitriol acts via its receptor (VDR) and inhibits PTH secretion and parathyroid cell proliferation. Increased prevalence of the polymorphic VDR alleles b, a, and T has been demonstrated in sporadic primary hyperparathyroidism. Sixty-two patients with primary hyperparathyroidism due to parathyroid adenoma (mean age, 69.5 ± 1.4 yr) were genotyped for these VDR polymorphisms. Dispersed cells of the adenomas were exposed to increasing concentrations of extracellular Ca2+ and analyzed for PTH release and cytoplasmic Ca2+ concentrations. Ca2+-mediated PTH inhibition exhibited higher ED50 and less suppression in the cells of patients who were homozygous for the b, a, and T alleles (P &lt; 0.05–0.10). When analyzing haplotypes, the patients with baT demonstrated a ED50 of 1.81 ± 0.15 vs. 1.29 ± 0.10 for BAt (P &lt; 0.05). As VDR alleles were unrelated to parathyroid intracellular Ca2+, influences of polymorphic VDR alleles on PTH secretion seem to involve mechanisms other than the Ca2+-sensing protein of the parathyroid cell surface.
Prevention of Early Postmenopausal Bone Loss with Cyclical Etidronate Therapy (A Double-Blind, Placebo-Controlled Study and 1-Year Follow-Up)*
Authors: Meunier P. J. , Confavreux E. , Tupinon I. , Hardouin C. , Delmas P. D. , Balena R. 
Published: January 2014

AbstractThe objective of the study was to evaluate the effects of cyclical therapy with etidronate and calcium on spinal and femoral bone loss in the early post menopausal period. Fifty-four women, 53 ± 2.8 yr old (mean ± sd) and 2.3 ± 1.3 yr post menopause received oral doses of either 400 mg/day etidronate for 2 weeks followed by 500 mg/day elemental calcium for 11 weeks, or placebo for 14 days followed by calcium for 11 weeks, repeated over a total of 24 months. A statistically significant increase in spinal bone mineral density (BMD) was observed after 6 months in the etidronate group. At 2 yr, the mean treatment differences in spinal and femoral neck BMD were+ 2.93% (P &lt; 0.02) and 2.02% (P &lt; 0.03), respectively. Serum osteocalcin and urinary crossLaps/creatinine excretion were decreased signficantly by etidronate. Etidronate was well tolerated with a safety profile similar to that of placebo.Thirty-seven women participated in a 1-yr open-label follow-up study. Twelve months after treatment withdrawal, spinal BMD in the former etidronate group decreased by 1.43% and serum osteocalcin and urinary crossLaps returned to pretreatment values.In conclusion, cyclical etidronate is an effective therapy for the prevention of both trabecular and cortical bone loss in the early menopause and has a good safety profile.