bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ketosis-Prone Diabetes: Dissection of a Heterogeneous Syndrome Using an Immunogenetic and β-Cell Functional Classification, Prospective Analysis, and Clinical Outcomes
Authors: Maldonado Mario , Hampe Christiane S. , Gaur Lakshmi K. , D’Amico Susana , Iyer Dinakar , Hammerle Lisa P. , Bolgiano Douglas , Rodriguez Lucille , Rajan Arun , Lernmark Åke , Balasubramanyam Ashok 
Published: November 2003

AbstractKetosis-prone diabetes is heterogeneous. Its causes could include novel β-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for β-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of β-cell function and biochemical and clinical parameters. They were classified into four Aβ groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A−) and β-cell functional reserve (β+ or β−). The group distribution was: 18 A+β−, 23 A−β−, 11 A+β+, and 51 A−β+. Collectively, the two β− groups differed from the two β+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A−β− group differed from the A+β− group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A−β+ group differed from the A+β+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and β-cell functional reserve. Novel, nonautoimmune causes of β-cell dysfunction are likely to underlie the A−β+ and A−β− syndromes.
Increased Risk of Falls and Increased Bone Resorption in Elderly Men with Partial Androgen Deficiency: The MINOS Study
Authors: Szulc P. , Claustrat B. , Marchand F. , Delmas P. D. 
Published: November 2003

AbstractThe goal of this study was to identify the clinical and biological patterns of hypogonadism in a cohort of 1040 elderly men. Residual androgenic activity was estimated by total testosterone as well as the apparent free testosterone concentration (AFTC) and free testosterone index (FTI) calculated on the basis of concentrations of SHBG and total testosterone using appropriate formulae. The lower limit of the normal range defined by 2 sd below the mean in 150 healthy, nonobese, and nonsmoking men, aged 19–40 yr, was calculated for total testosterone (9.26 nmol/liter), AFTC (146 pmol/liter), and FTI (0.14 nmol/nmol). The prevalence of hypogonadism increased with ageing. Hypogonadal men were older and heavier (due to a higher fat body mass) and had lower concentrations of 17β-estradiol and androstenedione than men with normal androgenic activity. Men with decreased AFTC had a slightly lower bone mineral density (BMD) at certain sites. Men with decreased FTI had lower appendicular skeletal muscle mass and relative skeletal muscle index. For all three measures of androgenic activity, hypogonadal men had increased levels of the markers of bone resorption. In the multiple regression models including both 17β-estradiol and testosterone (total, AFTC, or FTI), 17β-estradiol was the only significant determinant of BMD. In the multiple regression models including 17β-estradiol and AFTC or FTI, only testosterone was a significant determinant of the variability in bone formation markers, whereas both 17β-estradiol and testosterone were significant determinants of the variability of the markers of bone resorption. Hypogonadism was associated with an increase in the risk of falls, an impairment of static and dynamic balance, as well as the inability to stand up from a chair and to perform the tandem walk. Decreased AFTC (&lt;146 pmol/liter) discriminated best men with functional disabilities (odds ratio, 1.54–7.95; P &lt; 0.05–0.0001). Hypogonadal elderly men had increased bone resorption that was not adequately matched by an increase in bone formation, lower muscle strength, impaired static and dynamic balance, a higher risk of falls, and, in men with low AFTC, a slightly lower BMD. Low AFTC seems to have the best discriminative power for densitometric, biochemical, and functional parameters, followed by FTI, whereas total testosterone was the least discriminative. In multiple regression models, 17β-estradiol was the strongest determinant of BMD, and AFTC and FTI were significant determinants of the variability in bone formation markers, whereas both 17β-estradiol and testosterone determined the variability in bone resorption markers.
Adolescents with Partial Growth Hormone (GH) Deficiency Develop Alterations of Body Composition after GH Discontinuation and Require Follow-Up
Authors: Tauber Maithé , Jouret Béatrice , Cartault Audrey , Lounis Nadia , Gayrard Michèle , Marcouyeux Corinne , Pienkowski Catherine , Oliver Isabelle , Moulin Pierre , Otal Philippe , Joffre Francis , Arnaud Catherine , Rochiccioli Pierre 
Published: November 2003

AbstractIt is now a consensus to resume GH treatment in adolescents with severe GH deficiency (GHD) at retesting to prevent the occurrence of adult GHD syndrome. However, we do not have any data on the follow-up of adolescents with nonsevere GHD at completion of treatment. This report presents preliminary data from a 1-yr prospective study that includes the first 91 patients retested. Anthropometric data, IGF-I and IGF binding protein-3 levels, glycemia and insulinemia, lipid profile, and body composition using dual x-ray absorptiometry and abdominal computed tomography scan were recorded at completion of GH treatment and 1 yr later. Body composition was significantly different at both evaluations, with increased total body fat and decreased lean body mass in the partial GHD group vs. the normal group. Moreover, these alterations worsened after 1 yr without GH in the partial GHD group, whereas there were no modifications in the normal group. We did not find any metabolic alterations such as elevated triglyceride, total cholesterol, or insulin levels. Adolescents with reconfirmed partial GHD exhibit alterations in body composition after 1 yr without GH, whereas those retested normal do not. These changes are similar to those described in severe GHD, although less marked, and justify a precise follow-up.
Antecedent Adrenaline Attenuates the Responsiveness to But Not the Release of Counterregulatory Hormones during Subsequent Hypoglycemia
Authors: de Galan Bastiaan E. , Rietjens Saskia J. , Tack Cees J. , van der Werf Sieberen P. , Sweep C. G. J. (Fred) , W. M. Lenders Jacques , Smits Paul 
Published: November 2003

Abstract
Hypoglycemia unawareness is thought to be the consequence of recurrent hypoglycemia, yet the underlying mechanism is still incompletely understood. The aim of the present study was to determine the role of antecedent elevated adrenaline in the pathogenesis of hypoglycemia unawareness. Sixteen healthy volunteers (eight of either sex) participated in two experiments, performed in random order and at least 3 wk apart. During the morning, three consecutive doses of 0.04, 0.06, and 0.08 μg·kg−1·min−1 of adrenaline or matching placebo (normal saline) were infused for the total duration of 1 h. Three hours later, a hyperinsulinemic (360 pmol·m−2·min−1) two-step hypoglycemic (5.0–3.5–2.5 mmol·liter−1) clamp study was performed. During hypoglycemia, hypoglycemic symptoms, counterregulatory hormones, cardiovascular responses, and cognitive function were monitored. Hypoglycemia induced similar responses of autonomic and neuroglycopenic symptoms, counterregulatory hormones, and lengthening in reaction time on the choice reaction time task, irrespective of antecedent infusions. However, prior adrenaline was associated with higher exogenous glucose requirements at hypoglycemic nadir (10.1 ± 1.3 vs. 7.3 ± 1.3 μmol·kg−1·min−1, P = 0.017), an attenuated hypoglycemia-induced fall in blood pressure (mean arterial pressure, −13 ± 2 vs. −8 ± 2 mm Hg, P = 0.006), and preserved cognitive function as assessed by the symbol digit test during hypoglycemia, when compared with prior placebo. We conclude that elevated adrenaline attenuates the responsiveness to, but not the release of counterregulatory hormones during subsequent hypoglycemia. As such, adrenaline’s role in the development of hypoglycemia unawareness is limited.
Serum Osteoprotegerin as a Determinant of Bone Metabolism in a Longitudinal Study of Human Pregnancy and Lactation
Authors: Naylor K. E. , Rogers A. , Fraser R. B. , Hall V. , Eastell R. , Blumsohn A. 
Published: November 2003

AbstractOsteoprotegerin (OPG) is a soluble decoy receptor that inhibits bone resorption by binding to receptor activator of nuclear factor κB ligand. Murine studies suggest that OPG is elevated in pregnancy, but its role in human pregnancy is unknown. We evaluated the relationship among OPG, bone turnover, and bone density in a longitudinal study of planned human pregnancy and lactation (n = 17; age, 20–36 yr). Samples were collected before conception; at 16, 26, and 36 wk gestation; and at 2 and 12 wk postpartum. Indexes of bone resorption included serum β C-terminal and urinary N-terminal (uNTX) telopeptides of type I collagen. OPG increased by 110 ± 16% (mean ± sem) at 36 wk (P &lt; 0.001), followed by a rapid postpartum decline in both lactating and nonlactating women. Bone resorption was elevated at 36 wk (serum β C-terminal telopeptides by 76 ± 17%; urinary N-terminal telopeptides by 219 ± 41%; P &lt; 0.001). The tissue source of OPG in pregnancy is unknown. Human breast milk contains large amounts of OPG (162 ± 58 ng/ml in milk vs. 0.42 ± 0.03 ng/ml in nonpregnant serum). However, the rapid postpartum decline in serum OPG and the low serum OPG in neonates suggest a placental source. There was no correlation between change in OPG and bone turnover or bone mineral density (P &gt; 0.05), and the physiological importance of elevated OPG in human pregnancy remains uncertain.
Myostatin Is a Skeletal Muscle Target of Growth Hormone Anabolic Action
Authors: Liu Wei , Thomas Scott G. , Asa Sylvia L. , Gonzalez-Cadavid Nestor , Bhasin Shalendar , Ezzat Shereen 
Published: November 2003

Abstract
Myostatin is a cytokine that has recently been shown to selectively and potently inhibit myogenesis. To investigate the mechanisms of anabolic actions of GH on skeletal muscle growth, we examined the in vitro and in vivo effects of GH on myostatin regulation. Twelve GH-deficient hypopituitary adult subjects were treated with recombinant GH (5 μg/kg·d) in a double-blind, placebo-controlled fashion. Body composition and physical function were assessed and skeletal muscle biopsies from the vastus lateralis performed at 6-monthly intervals during 18 months of treatment. Myostatin mRNA expression was significantly inhibited to 31 ± 9% (P &lt; 0.001) of control by GH but not by placebo administration (79 ± 11%) as determined by quantitative real-time PCR normalized for the housekeeping glyceraldehyde-3-phosphate dehydrogenase gene. The inhibitory effect of GH on myostatin was sustained after 12 and 18 months of GH treatment. These effects were associated with increases in lean body mass and translated into enhanced aerobic performance as determined by maximal oxygen uptake and ventilation threshold. Parallel in vitro studies of skeletal muscle cells demonstrated significant reduction of myostatin expression by myotubes in response to GH, compared with vehicle treatment. Conversely, GH receptor antagonism resulted in up-regulation of myostatin in myoblasts. Given the potent catabolic actions of myostatin, our data suggest that myostatin represents a potential key target for GH-induced anabolism.
Estimating the Contribution of the Prostate to Blood Dihydrotestosterone
Authors: Toorians Arno W. F. T. , Kelleher Sharyn , Gooren Louis J. , Jimenez Mark , Handelsman David J. 
Published: November 2003

AbstractThe prostate strongly expresses type 2 5α-reductase, which avidly converts on entry most testosterone (T) to 5α-dihydrotestosterone (DHT). However, the quantitative contribution of the prostate to blood DHT is uncertain. We evaluated prostatic contribution to blood DHT by comparing the blood DHT concentrations in androgen-deficient patients with or without a prostate while they were receiving standard dose of T replacement. Androgen-deficient males (ADM) and female to male (F2M) transsexuals were studied in 2 centers, with both groups receiving either testosterone ester injections (250 mg mixed T esters) every 1 wk (Amsterdam) or 800 mg subdermal T implantation (Sydney). Among 39 Dutch patients, F2M (n = 21) were younger and smaller in physique than ADM (n = 18). One week (±1 d) after an injection, plasma DHT concentrations were 1.6 ± 0.2 (F2M) vs. 1.4 ± 0.2 (ADM) nmol/liter (P = 0.47), but the postinjection time interval to blood sampling was shorter in F2M (5.9 ± 0.4 vs. 7.2 ± 0.3 d; P = 0.01). Covariance adjustment for time since last injection, age, and physique did not change the lack of significant difference in postinjection plasma DHT concentration. The rapid and wide excursions in plasma T concentrations after an im T ester injection make the timing of blood sampling critical. To remove confounding by this variable, the experiment was repeated at a second site in similar patients, but using a depot T that achieves steady-state delivery for prolonged periods. Among 29 Australian patients, before and 1 month after subdermal implantation of 800 mg T, plasma DHT concentrations were not significantly different between groups [F2M, 1.1 ± 0.1 (n = 14); ADM, 1.3 ± 0.1 (n = 15); P = 0.28]. Correction for covariates, including age, height, weight, body surface area, and body mass index, did not influence the lack of significant difference between treated groups. As both modes of T administration yielded similar plasma DHT concentrations regardless of the presence of a prostate, this study indicates that the normal human prostate is not a major contributor to circulating blood DHT concentrations.
Endocrine Status in Patients with Optic Nerve Hypoplasia: Relationship to Midline Central Nervous System Abnormalities and Appearance of the Hypothalamic-Pituitary Axis on Magnetic Resonance Imaging
Authors: Birkebæk N. H. , Patel L. , Wright N. B. , Grigg J. R. , Sinha S. , Hall C. M. , Price D. A. , Lloyd I. C. , Clayton P. E. 
Published: November 2003

AbstractWe here: 1) describe the phenotypic spectrum, including magnetic resonance imaging (MRI) appearances of the pituitary stalk and anterior and posterior pituitary [H-P (hypothalamic-pituitary) axis], in children with optic nerve hypoplasia (ONH) with or without an abnormal septum pellucidum (SP); and 2) define endocrine dysfunction according to the MRI findings. Medical records of 55 children with ONH who had been assessed by ophthalmology and endocrine services were reviewed. All had MRI of the brain and H-P axis.Forty-nine percent of the ONH patients had an abnormal SP on MRI, and 64% had a H-P axis abnormality. Twenty-seven patients (49%) had endocrine dysfunction, and 23 of these had H-P axis abnormality. The frequency of endocrinopathy was higher in patients with an abnormal SP (56%) than a normal SP (39%). Patients were divided into four groups based on SP and H-P axis appearance: 1) both normal; 2) abnormal SP and normal H-P axis; 3) normal SP and abnormal H-P axis; and 4) both abnormal. The frequency of multiple pituitary hormone deficiency was highest (56%) in group 4, lower (35%) in group 3, and even lower (22%) in group 2. Precocious puberty was most common in group 2. None of the patients in group 1 had endocrine dysfunction. Thus, SP and H-P axis appearances on MRI can be used to predict the likely spectrum of endocrinopathy.
Elevated Physical Activity and Low Leptin Levels Co-occur in Patients with Anorexia Nervosa
Authors: Holtkamp Kristian , Herpertz-Dahlmann Beate , Mika Claudia , Heer Martina , Heussen Nicole , Fichter Manfred , Herpertz Stephan , Senf Werner , Blum Werner F. , Schweiger Ulrich , Warnke Andreas , Ballauff Anne , Remschmidt Helmut , Hebebrand Johannes 
Published: November 2003

Abstract
Low leptin levels are an endocrinological hallmark of acute anorexia nervosa (AN); a subthreshold leptin secretion in adipocytes as a consequence of a reduced energy intake is presumed to be the major trigger of the adaptation of an organism to semistarvation. The aim of the current study is to define symptoms of AN that are potentially linked to low leptin levels. For this purpose, quantitative somatic and psychopathological variables were obtained in 61 inpatients with acute AN (study group 1) upon referral for inpatient treatment, and they were concomitantly blood sampled to allow determination of serum leptin levels. Correlations between these variables and logarithmic transformed (lg10) leptin levels were descriptively assessed. Apart from the well-known correlations between leptin levels and anthropometric measurements, the strongest correlation was observed between lg10 serum leptin levels and expert ratings of motor restlessness (r = −0.476; nominal P = 0.003) upon use of visual analog scales. We thus generated the hypothesis that physical activity levels in AN patients are related to serum leptin levels. This hypothesis was tested in an independent study group of 27 adolescent inpatients (study group 2) who were also assessed upon referral. Physical activity levels, which, in this study group, were assessed with the activity module of the expert rating form of the Structured Inventory for Anorexic and Bulimic Syndromes, were significantly correlated with lg10 leptin levels (r = −0.51; one-sided P = 0.006). A regression model based on the independent variables body mass index and lg10 leptin levels explained 37% of the variance of physical activity (R2 = 0.37; P = 0.003); only the lg10 leptin levels contributed significantly to the variance (P = 0.003). Our results suggest that, similar to semistarvation-induced hyperactivity in rats, hypoleptinemia in patients with AN may be one important factor underlying the excessive physical activity.
Effects of Bezafibrate and Simvastatin on Endothelial Activation and Lipid Peroxidation in Hypercholesterolemia: Evidence of Different Vascular Protection by Different Lipid-Lowering Treatments
Authors: Desideri Giovambattista , Croce Giuseppe , Tucci Marzia , Passacquale Gabriella , Broccoletti Simona , Valeri Letizia , Santucci Anna , Ferri Claudio 
Published: November 2003

Abstract
Hypercholesterolemia is combined with enhanced lipid peroxidation, which can promote atherogenesis by inducing endothelial adhesion molecule expression. Statins may protect vascular endothelium in hypercholesterolemia by reducing enhanced plasma levels of low-density lipoprotein and decreasing oxidative stress. Herein, we describe increased circulating levels of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin and total 8-iso-prostaglandin F2α (8-iso-PGF2α) concentrations, as indexes of endothelial activation and lipid peroxidation, respectively, in 67 hypercholesterolemic patients compared with 32 normocholesterolemic subjects. Significant cholesterol reductions were achieved in hypercholesterolemic patients after 6 months under either simvastatin (40 mg/d) or bezafibrate (800 mg/d) treatment, given according to a randomized double-blind trial. Simvastatin but not bezafibrate simultaneously reduced soluble adhesin and total 8-iso-PGF2α concentrations also. Vitamin E supplementation (400 IU/d) further reduced indexes of endothelial activation and lipid peroxidation in simvastatin-treated patients and significantly reduced the above indexes in bezafibrate-treated patients. Changes in circulating soluble adhesion molecule levels were directly correlated with changes in total 8-iso-PGF2α concentrations in simvastatin-treated patients also receiving vitamin E supplementation. All together, our data demonstrated that hypercholesterolemia was combined with endothelial activation and lipid peroxidation, which were efficaciously counteracted by simvastatin but not bezafibrate treatment. Thus, a different vascular protection can be achieved by different lipid-lowering treatments.
Muscle Oxidative Capacity Is a Better Predictor of Insulin Sensitivity than Lipid Status
Authors: Bruce Clinton R. , Anderson Mitchell J. , Carey Andrew L. , Newman David G. , Bonen Arend , Kriketos Adamandia D. , Cooney Gregory J. , Hawley John A. 
Published: November 2003

AbstractWe determined whole-body insulin sensitivity, long-chain fatty acyl coenzyme A (LCACoA) content, skeletal muscle triglyceride (TGm) concentration, fatty acid transporter protein content, and oxidative enzyme activity in eight patients with type 2 diabetes (TYPE 2); six healthy control subjects matched for age (OLD), body mass index, percentage of body fat, and maximum pulmonary O2 uptake; nine well-trained athletes (TRAINED); and four age-matched controls (YOUNG). Muscle biopsies from the vastus lateralis were taken before and after a 2-h euglycemic-hyperinsulinemic clamp. Oxidative enzyme activities, fatty acid transporters (FAT/CD36 and FABPpm), and TGm were measured from basal muscle samples, and total LCACoA content was determined before and after insulin stimulation. Whole-body insulin-stimulated glucose uptake was lower in TYPE 2 (P &lt; 0.05) than in OLD, YOUNG, and TRAINED. TGm was elevated in TYPE 2 compared with all other groups (P &lt; 0.05). However, both basal and insulin-stimulated skeletal muscle LCACoA content were similar. Basal citrate synthase activity was higher in TRAINED (P &lt; 0.01), whereas β-hydroxyacyl CoA dehydrogenase activity was higher in TRAINED compared with TYPE 2 and OLD. There was a significant relationship between the oxidative capacity of skeletal muscle and insulin sensitivity (citrate synthase, r = 0.71, P &lt; 0.001; β-hydroxyacyl CoA dehydrogenase, r = 0.61, P = 0.001). No differences were found in FAT/CD36 protein content between groups. In contrast, FABPpm protein was lower in OLD compared with TYPE 2 and YOUNG (P &lt; 0.05). In conclusion, despite markedly elevated skeletal muscle TGm in type 2 diabetic patients and strikingly different levels of whole-body glucose disposal, both basal and insulin-stimulated LCACoA content were similar across groups. Furthermore, skeletal muscle oxidative capacity was a better predictor of insulin sensitivity than either TGm concentration or long-chain fatty acyl CoA content.
BRAF Mutations in Thyroid Tumors Are Restricted to Papillary Carcinomas and Anaplastic or Poorly Differentiated Carcinomas Arising from Papillary Carcinomas
Authors: Nikiforova Marina N. , Kimura Edna T. , Gandhi Manoj , Biddinger Paul W. , Knauf Jeffrey A. , Basolo Fulvio , Zhu Zhaowen , Giannini Riccardo , Salvatore Giuliana , Fusco Alfredo , Santoro Massimo , Fagin James A. , Nikiforov Yuri E. 
Published: November 2003

Abstract
Activating point mutations of the BRAF gene have been recently reported in papillary thyroid carcinomas. In this study, we analyzed 320 thyroid tumors and six anaplastic carcinoma cell lines and detected BRAF mutations in 45 (38%) papillary carcinomas, two (13%) poorly-differentiated carcinomas, three (10%) anaplastic carcinomas, and five (83%) thyroid anaplastic carcinoma cell lines but not in follicular, Hürthle cell, and medullary carcinomas, follicular and Hürthle cell adenomas, or benign hyperplastic nodules. All mutations involved a T→A transversion at nucleotide 1796. In papillary carcinomas, BRAF mutations were associated with older age, classic papillary carcinoma or tall cell variant histology, extrathyroidal extension, and more frequent presentation at stages III and IV. All BRAF-positive poorly differentiated and anaplastic carcinomas contained areas of preexisting papillary carcinoma, and mutation was present in both the well-differentiated and dedifferentiated components. These data indicate that BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas. They are associated with distinct phenotypical and biological properties of papillary carcinomas and may participate in progression to poorly differentiated and anaplastic carcinomas.