bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotype and Genetic Analysis of a Syndrome Caused by an Inactivating Mutation in the Growth Hormone-Releasing Hormone Receptor: Dwarfism of Sindh1
Authors: Maheshwari Hiralal G. , Silverman Bernard L. , Dupuis Josée , Baumann Gerhard 
Published: January 2014

We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 sd below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 sd, and blood pressure approximately 3 sd below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, l-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 ± 2.0 ng/mL and 0.42 ± 0.13 μg/mL, respectively; mean ± sd) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50→Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and l-dopa, but they showed only minimal or no height deficit.This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.
Bone Mineral Recovery after Parathyroidectomy in Patients with Primary and Renal Hyperparathyroidism
Authors: Abdelhadi Mohamed , Nordenström Jörgen 
Published: January 2014

Patients with hyperparathyroidism (HPT) generally display reduced bone mass due to excessive PTH activity. The effect of parathyroidectomy on bone mass changes in different types of HPT, however, is not well understood. Bone mineral density (BMD) was measured in the distal radius, total body, femoral neck, and lumbar spine by dual energy x-ray absorptiometry in four groups of patients with different hyperparathyroid conditions: primary symptomatic HPT (n = 54), primary asymptomatic (mild) HPT (n = 24), HPT associated with hemodialysis (n = 20), and HPT associated with renal transplant (n = 30). Subsets of patients with primary symptomatic HPT (n= 52), HPT associated with hemodialysis (n = 19), and HPT associated with renal transplant (n = 15) underwent parathyroidectomy, and bone density was measured longitudinally for 3 yr. Patients with primary asymptomatic (mild) HPT did not undergo surgery and were followed prospectively.Before surgery, all groups showed a greater reduction of bone mineral density in cortical bone (distal radius) than in predominantly trabecular bone (lumbar spine). In primary symptomatic HPT, the BMD z-score of the distal radius was −1.80 ± 0.21 (±sem), and the corresponding figures for the total body, femoral neck, and lumbar spine were −0.60 ± 0.15, −0.54 ± 0.14, and −0.53 ± 0.18 compared with those of an age- and sex-matched reference group. In renal HPT BMD z-scores were −2.51± 0.38 (hemodialysis patients) and −2.83 ± 0.43 (renal transplant patients) for the distal radius and between −0.81 and− 1.46 for the other measured sites.After parathyroidectomy, BMD increased by 1–8% at all sites in patients with primary symptomatic HPT and HPT associated with renal transplant. The largest increase in bone mass was observed in patients with HPT associated with hemodialysis, in whom the improvement amounted to 7–23%. In patients with primary HPT and HPT associated with hemodialysis, this increase in bone density resulted in virtual recovery from their preoperative bone loss. The majority of patients with asymptomatic primary HPT disease (n = 21) maintained their bone density during the follow-up period and have not shown evidence of increases in serum calcium or PTH levels, but three patients followed conservatively underwent parathyroidectomy due to progressive deterioration of BMD.We conclude that, regardless of the etiology, a large proportion of HPT patients show reduced bone density. In patients with primary symptomatic HPT and patients with HPT associated with hemodialysis, bone density increases after parathyroidectomy to an extent that largely restores the preoperative bone loss. However, no anabolic effect of parathyroidectomy on bone mass was observed in patients with HPT associated with renal transplant, probably because of their immunosuppressive therapy.
Effect of Early Referral to an Endocrinologist on Efficiency and Cost of Evaluation and Development of Treatment Plan in Patients with Thyroid Nodules
Authors: Ortiz Robert , Hupart Kenneth H. , DeFesi Charles R. , Surks Martin I. 
Published: January 2014

Radionuclide uptake and scan and sonogram, frequently ordered before referral to an endocrinologist, are expensive and poor predictors of thyroid nodule malignancy. We estimated costs of excessive imaging and other studies by reviewing the records of all patients (n = 70) referred to a single, consulting endocrinologist, for thyroid nodule evaluation in a 2-yr interval and subsequently, presenting only pertinent histories and results of physical examinations, thyroid function tests, and thyroid autoantibodies, to a second, reviewing endocrinologist (RE) who was blinded to diagnosis and management. Concordance in diagnosis and management between consulting endocrinologist and RE was 87.1% and 93.4%, respectively. Accuracy of diagnosis, loss of patient’s time (8.7 h, average), and cost of unnecessary testing, defined as tests not required by the RE for diagnosis and management according to published guidelines, were determined. Unnecessary testing included 153 physician’s office or diagnostic laboratory visits, 44 sets of thyroid function tests, 32 radionuclide uptake and scan, 39 thyroid sonograms, and 3 computed tomography scans. The total direct cost of unnecessary tests was estimated at $27,290 ($390/patient) in addition to costs of 30 unnecessary physician’s office visits. Only 2 of 8 surgical referrals required surgery, whereas 6 other patients required surgery, including 3 with papillary carcinoma. We conclude that early referral to an endocrinologist of patients with suspected thyroid nodules results in significant savings in cost of evaluation, patient’s time, and increased diagnostic precision. Six of the 8 patients referred for surgery before endocrine consultation had benign thyroid disease that did not require surgery. Six additional patients were referred to surgery, 3 of whom had papillary thyroid carcinoma.
Early referral of patients with suspected thyroid nodules to an endocrinologist results in significant savings in both cost and patient’s time as well as increased precision of diagnosis.
Relation among Left Ventricular Mass, Insulin Resistance, and Blood Pressure in Nonobese Subjects1
Authors: Phillips Robert A. , Krakoff Lawrence R. , Dunaif Andrea , Finegood Diane T. , Gorlin Richard , Shimabukuro Seiichi 
Published: January 2014

Because left ventricular (LV) mass (LVM) is a powerful predictor of future cardiovascular events, it is important to identify hemodynamic and nonhemodynamic factors that increase LVM. We studied the separate contribution to LVM of daily arterial blood pressure (BP) and insulin resistance in a consecutive series of 29 (mean ± sd age, 43 ± 13 yr) nonobese (body mass index, 24 ± 1.8 kg/m2), nondiabetic, glucose-tolerant subjects with untreated borderline or mild hypertension. The insulin sensitivity index (SI) was quantitatively determined from the frequently sampled iv glucose tolerance test. BP was characterized by ambulatory 24-h BP monitoring, and LVM index (LVMI) was determined by two-dimensional directed M-mode echocardiography. LVMI was directly related to 24-h mean BP (r = 0.47; P = 0.01). LMVI was also significantly related to SI (r = −0.43; P = 0.02). In this nonobese group, neither LVMI nor SI was related to body mass index or age. After adjustment for the influence of BP on LVMI, a significant relation remained between LVMI and SI (P &lt; 0.05).
We conclude that in nonobese subjects with high normal BP, insulin sensitivity is related to LVM independently of BP and may be an important modulator of LV growth. In addition to a reduction of arterial BP, optimal prevention of LV hypertrophy in hypertensives may require improved insulin sensitivity.
The Effect of Age and Glycemic Level on the Response of theβ -Cell to Glucose-Dependent Insulinotropic Polypeptide and Peripheral Tissue Sensitivity to Endogenously Released Insulin1
Authors: Meneilly Graydon S. , Ryan Alice S. , Minaker Kenneth L. , Elahi Dariush 
Published: January 2014

abstract
Normal aging is characterized by a progressive impairment in glucose tolerance. An important mechanism underlying the glucose intolerance of aging is an impairment in glucose-induced insulin release. These studies were conducted to determine whether the age-related impairment in insulin release was caused by a decreased β-cell sensitivity to glucose-dependent insulinotropic polypeptide (GIP). Thirty-one Caucasian men were divided into four groups: two young groups (age range: 19–26 yr, n = 15) and two old groups (age range: 67–79 yr, n = 16). Each volunteer participated in three studies (n= 93 clamps). Hyperglycemic clamps were conducted at two doses [basal plasma glucose (G) + 5.4 mmol/L and G + 12.8 mmol/L] for 120 min. In the initial hyperglycemic clamp, only glucose was infused. In subsequent studies, GIP was infused at a final rate of 2 or 4 pmol/kg−1·min−1 from 60–120 min. Basal plasma insulin and GIP levels were similar in the young (41 ± 6 and 51 ± 6 pmol/L) and the old subjects (42 ± 6 and 66± 12 pmol/L) in all studies. First- and second-phase insulin responses were similar during the control study and during the first 60 min of each GIP infusion study in both groups. The 90–120 min GIP values were similar between groups and between hyperglycemic plateaus during the 2 and 4 pmol/kg−1·min−1 GIP infusion (young: 342 ± 28 and 601 ± 44 pmol/L, old: 387 ± 45 and 568 ± 49 pmol/L). In response to the GIP infusions, significant increases in insulin occurred in young and old at both glucose levels (P &lt; 0.01). The potentiation of the insulin response caused by GIP was greater in the young subjects than in the old, in the G + 5.4 mmol/L studies (P &lt; 0.05). However, the insulin response to GIP was similar in both young and old during the G + 12.8 mmol/L clamps. The insulinotropic effect of the incretin was higher in the young and in the old, in the G + 12.8 mmol clamps, than in the G + 5.4 mmol/L clamps.
We conclude that normal aging is characterized by a decreased β-cell sensitivity to GIP during modest hyperglycemia, which may explain, in part, the age-related impairment in glucose-induced insulin release. We also find that the insulinotropic effect of GIP is increased with increasing levels of hyperglycemia.
Identification of Novel High Molecular Weight Insulin-Like Growth Factor-Binding Protein-3 Association Proteins in Human Serum1
Authors: Collett-Solberg Paulo F. , Nunn Steven E. , Gibson Tara Beers , Cohen Pinchas 
Published: January 2014

abstractThe insulin-like growth factor (IGF)-binding proteins (IGFBPs) carry IGFs in serum and regulate their activity and bioavailability. The main IGFBP in serum, IGFBP-3, is known to form a 150-kDa complex with IGFs and the acid-labile subunit (ALS).We investigated the binding of IGFBP-3 to additional association proteins in human serum (IGFBP-3 APs). Ligand blots, column chromatography, and affinity cross-linking experiments revealed the specific binding of IGFBP-3 to at least three novel serum proteins. These techniques demonstrated the presence of proteins with molecular masses of 70, 100, and 150 kDa that bind IGFBP-3 with high affinity. Serum ALS migrated separately (at 88 kDa) from the novel IGFBP-3 APs (as evident by Western immunoblot), and bound IGFBP-3 weakly (by reverse ligand blots). We also demonstrated that large amounts of one of the IGFBP-3 APs and small amounts of ALS were coimmunoprecipitated with IGFBP-3 from human serum. Similar to ALS, these IGFBP-3 APs are acid labile and lose their IGFBP-3 binding capacity after exposure to low pH.We conclude that there are several serum proteins in addition to ALS and IGFs that bind IGFBP-3 with high affinity. These IGFBP-3 APs may serve as an additional reservoir of IGFBP-3 or modulate its functions.
Menstrual Abnormalities in Women with Cushing’s Disease Are Correlated with Hypercortisolemia Rather Than Raised Circulating Androgen Levels
Authors: Lado-Abeal J. , Rodriguez-Arnao J. , Newell-Price J. D. C. , Perry L. A. , Grossman A. B. , Besser G. M. , Trainer P. J. 
Published: January 2014

Menstrual irregularity is a common complaint at presentation in women with Cushing’s syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16–41 yr) with newly diagnosed pituitary-dependent Cushing’s syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26–30 days), oligomenorrhea (OL; 31–120 days), amenorrhea (AM; &gt;120 days), and polymenorrhea (PM; &lt;26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 μg GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests.
Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P &lt; 0.05) or NC patients (279 pmol/L; P &lt; 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P &lt; 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P &lt; 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P &lt; 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = −0.50; P &lt; 0.01) and 1800 h (r = −0.56; P &lt; 0.01) and with mean cortisol (r = −0.46; P &lt; 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter.
In summary, in our study 80% of patients with Cushing’s syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing’s disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.
Decreased Nitric Oxide Levels and Bone Turnover in Amenorrheic Athletes with Spinal Osteopenia1
Authors: Stacey E. , Korkia P. , Hukkanen M. V. J. , Polak J. M. , Rutherford O. M. 
Published: January 2014

Amenorrheic athletes have been likened to postmenopausal women, with low estrogen levels and osteopenia. It has been suggested that estrogen exerts its antiresorptive actions on bone via a nitric oxide (NO)-dependent mechanism. This study investigated whether the mechanism of bone loss in amenorrheic athletes is similar to that of postmenopausal women with reduced NO levels and high bone turnover.
Eleven amenorrheic athletes, 15 eumenorrheic athletes, and 10 sedentary controls were studied. Spine and hip bone mineral density was measured using dual-energy x-ray absorptiometry. Bone turnover was assessed by biochemical markers of formation (osteocalcin and bone-specific alkaline phosphatase) and resorption (deoxypyridinoline). NO metabolites were measured from 24-h urine samples using a chemiluminescence assay.
Spine, but not hip, bone mineral density was reduced in the amenorrheic group, compared with the eumenorrheic (P = 0.0001) and control (P = 0.04) groups. Osteocalcin, bone-specific alkaline phosphatase, and deoxypyridinoline were similar in all groups. NO metabolites were lower in the amenorrheic group, compared with controls (P = 0.035), despite a higher dietary intake of nitrates.
Unlike postmenopausal women, amenorrheic athletes do not have raised bone turnover but do have reduced NO metabolites and spinal osteopenia. The results show, however, that reduced NO production is a common denominator in both conditions and further support the importance of NO in estrogen-mediated protection of skeletal mass and strength.
Activation of Central Neuropeptide Y Y1 Receptors Potently Stimulates Food Intake in Male Rhesus Monkeys*
Authors: Larsen P. J. , Tang-Christensen M. , Stidsen C. E. , Madsen K. , Smith M. S. , Cameron J. L. 
Published: January 2014

Abstract
The orexigenic role of central neuropeptide Y (NPY) in nonhuman primates has been questioned. Therefore, we have studied the effect of central NPY on feeding in ad libitum-fed male rhesus macaques. NPY dose-dependently increased food intake, with the maximal effect obtained by 50 μg (960 min food intake ± sem, 104 ± 5 to 188 ± 11 g; vehicle vs. NPY; n = 6). Blood glucose levels were unaffected by intracerebroventricular administration of NPY, but animals receiving either 20 or 50 μg displayed increased plasma levels of insulin and cortisol at few time points. To assess the pharmacological specificity of this response, a novel Y1 antagonist,[ (Ile,Glu,Pro,Daba,Tyr, Arg,Leu,Arg,Tyr-NH2)2 cyclic (2,4′),(2′,4)-diamide] (Y1ANT), was synthesized. Receptor binding experiments demonstrated that Y1ANT preferentially binds to Y1 and Y4 receptors (pKi 10.12 ± 0.06 and 9.11 ± 0.05 nmol/L, respectively). Functional analysis revealed that Y1ANT is a Y1 antagonist and a partial Y4 agonist. Central administration of Y1ANT blocked NPY-induced feeding. In food-deprived monkeys, Y1ANT attenuated the feeding response. However, Y1ANT had no effect on food intake in satiated monkeys. Thus, endogenous NPY is likely to be involved in the regulation of food intake in the nonhuman primate, and this effect is at least partially mediated via Y1-like receptors.
Inactivity Amplifies the Catabolic Response of Skeletal Muscle to Cortisol*
Authors: FERRANDO ARNY A. , STUART CHARLES A. , SHEFFIELD-MOORE MELINDA , WOLFE ROBERT R. 
Published: January 2014

Abstract
Severe injury or trauma is accompanied by both hypercortisolemia and prolonged inactivity or bed rest (BR). Trauma and BR alone each result in a loss of muscle nitrogen, albeit through different metabolic alterations. Although BR alone can result in a 2–3% loss of lean body mass, the effects of severe trauma can be 2- to 3-fold greater. We investigated the combined effects of hypercortisolemia and prolonged inactivity on muscle protein metabolism in healthy volunteers. Six males were studied before and after 14 days of strict BR using a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis and breakdown rates of skeletal muscle protein were also directly calculated. Each assessment of protein metabolism was conducted during a 12-h infusion of hydrocortisone sodium succinate (120 μg/kg·h), resulting in blood cortisol concentrations that mimic severe injury (≈31 μg/dL). After 14 days of strict BR, hypercortisolemia increased phenylalanine efflux from muscle by 3-fold (P &lt; 0.05). The augmented negative amino acid balance was the result of an increased muscle protein breakdown (P &lt; 0.05) without a concomitant change in muscle protein synthesis. Muscle efflux of glutamine and alanine increased significantly after bed rest due to a significant increase in de novo synthesis (P &lt; 0.05). Thus, inactivity sensitizes skeletal muscle to the catabolic effects of hypercortisolemia. Furthermore, these effects on healthy volunteers are analogous to those seen after severe injury.
A Novel Case of Multiple Endocrine Neoplasia Type 2A Associated with Two de Novo Mutations of the RETProtooncogene*
Authors: Tessitore Alessandra , Sinisi Antonio A. , Pasquali Daniela , Cardone Monica , Vitale Domenico , Bellastella Antonio , Colantuoni Vittorio 
Published: January 2014

AbstractWe report a novel case of multiple endocrine neoplasia type 2A (MEN 2A) associated with two mutations of the protooncogene RET. One affects codon 634 and causes a cysteine to arginine substitution; the second at codon 640 causes an alanine to glycine substitution in the transmembrane region. The two mutations were present on the same RET allele and were detected in germline and tumor DNA. Both mutations were de novo, i.e. they were not found in the DNA of the parents or relatives. Immunohistochemical and RT-PCR analysis showed that the pheochromocytoma expressed calcitonin as well as both RET alleles. A cell line established from the tumor and propagated in culture sustained the expression of RET and calcitonin, as did the original pheochromocytoma. Because the patient presented with medullary thyroid carcinoma and pheochromocytoma without parathyroid gland involvement, we speculate that this clinical picture could be correlated with the two RET mutations and to the unusual calcitonin production. This is the first report of a MEN 2A case due to two mutations of the RET gene and associated with a calcitonin-producing pheochromocytoma.