bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical Tests in the Diagnosis of Childhood Growth Hormone Deficiency*
Authors: Tillmann Vallo , Buckler John M. H. , Kibirige Mohammed S. , Price David A. , Shalet Stephen M. , Wales Jeremy K. H. , Addison Michael G. , Gill Mathew S. , Whatmore Andy J. , Clayton Peter E. 
Published: January 2014

Abstract
GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. We have examined, therefore, the performance of other tests of the GH axis[ urinary GH excretion, serum insulin-like growth factor I (IGF-I), and IGF-binding protein-3 (IGFBP-3) levels] compared with GH stimulation tests in identifying children defined clinically as GH deficient.
Group I comprised 60 children (mean age, 10.3 ± 4.8 yr) whose diagnosis of GHD was based on a medical history indicative of pituitary dysfunction (n = 43) or on the typical phenotypic features and appropriate auxological characteristics of isolated GHD (n = 17). Group II comprised 110 short children (mean age, 9.8 ± 4 yr) in whom GHD was not suspected, but needed exclusion.
The best sensitivity for a single GH test was 85% at a peak GH cut-off level of 10 ng/mL, whereas the best specificity was 92% at 5 ng/mL. The sensitivities of IGF-I, IGFBP-3, and urinary GH, using a cut-off of− 2 sd score were poor at 34%, 22%, and 25%, respectively, with specificities of 72%, 92%, and 76% respectively. Only 2 of 21 pubertal children in group I and none of the 27 subjects with radiation-induced GHD had an IGFBP-3 sd score less than −1.5. We devised a scoring system based on the positive predictive value of each test, incorporating data from the GH test and the IGF-I and IGFBP-3 levels. A specificity of 94% could be achieved with a score of 10 or more (maximum 17) (sensitivity 34%). The latter could not be improved above 81% with a score of 5 points or more (specificity, 69%).
A high score was, therefore, highly indicative of GHD, but was achieved by few patients. A normal IGFBP-3 level, however, did not exclude GHD, particularly in patients with radiation-induced GHD and those in puberty. A GH test with a peak level more than 10 ng/mL was the most useful single investigation to exclude a diagnosis of GHD.
15-Hydroxyprostaglandin Dehydrogenase: Implications in Preterm Labor with and without Ascending Infection1
Authors: van Meir Claudia A. , Matthews Stephen G. , Keirse Marc J. N. C. , Ramirez Mildred M. , Bocking Alan , Challis John R. G. 
Published: January 2014

AbstractThere is evidence that intrauterine infection, which stimulates PG synthesis may play a role in the pathogenesis of some preterm labor. Local tissue concentrations of PGs are controlled not only by the rate of synthesis, but also by catabolism, which is regulated by 15-hydroxyprostaglandin dehydrogenase (PGDH). We hypothesized that a decrease of PGDH activity could contribute to an increase in PG output at the time of preterm labor (PTL) especially in association with infection. We measured PGDH activity with a zero order kinetic enzymatic assay, PGDH messenger ribonucleic acid by in situ hybridization and PGDH distribution and localization with immunohistochemistry in human placenta and fetal membranes from women at term before (n = 10) or after (n = 16) labor compared to preterm labor at less than 36 weeks without (n = 16) and with (n = 11) chorioamnionitis. PGDH activity in chorion was significantly lower in PTL than at term and was further reduced when PTL was associated with inflammation. Immunoreactive PGDH and PGDH messenger ribonucleic acid localized predominantly to chorionic trophoblasts at term and were reduced in PTL women with or without infection. These effects were not observed in the placenta. Loss of PGDH with infection was associated with infiltration of chorion by polymorphonuclear leukocytes, resulting in a compromised structural integrity, although the amniotic epithelium was generally intact. We conclude that a reduction in PGDH in the human fetal membranes may occur in some cases of preterm labor and may contribute to an increase in net PG accumulation and drive to myometrial contractility.
The Longitudinal Course of Psychopathology in Cushing’s Syndrome after Correction of Hypercortisolism
Authors: Dorn Lorah D. , Burgess Ellen S. , Friedman Theodore C. , Dubbert Billinda , Gold Philip W. , Chrousos George P. 
Published: January 2014

Abstract
Endogenous Cushing’s syndrome (CS) is associated with significant psychopathology during the course of the disease. The purpose of this study was to evaluate the psychological and endocrine status of patients with CS after correction of their hypercortisolism. Thirty-three patients with active CS were examined before and at 3 months (28 patients), 6 months (25 patients), and 12 months (29 patients) after correction of hypercortisolism. Before cure, 66.7% of the patients had significant psychopathology, with the predominant diagnosis of atypical depressive disorder (AD) in 51.5% and/or major affective disorder in 12%. After cure, overall psychopathology decreased significantly to 53.6% at 3 months, 36% at 6 months, and 24.1% at 12 months, when there was a parallel recovery of the hypothalamic-pituitary-adrenal axis assessed by serial morning ACTH stimulation tests. There was an inverse correlation between psychological recovery and baseline morning cortisol, but no correlation with ACTH-stimulated cortisol values at 60 min. AD continued to be the prevailing diagnosis after correction of hypercortisolism, whereas the frequency of suicidal ideation and panic increased. The presence of AD before and after correction of hypercortisolism might be due to glucocorticoid-induced suppression of hypothalamic CRH secretion. The slight increase in the incidence of panic after correction of hypercortisolism might be due to a decreased glucocorticoid restraint at the central arousal/sympathetic catecholaminergic system. We conclude that CS is associated with AD symptomatology, which gradually improves with time after correction of hypercortisolism. Health care providers should be aware of changes in symptomatology, including suicidal ideation and panic attacks, that occur in a subgroup of patients.
II. Adrenal Cortex and Steroid 21-Hydroxylase Autoantibodies in Children with Organ-Specific Autoimmune Diseases: Markers of High Progression to Clinical Addison’s Disease
Authors: Betterle Corrado , Volpato Marina , Rees Smith Bernard , Furmaniak Jadwiga , Chen Shu , Zanchetta Renato , Greggio Nella A. , Pedini Beniamino , Boscaro Marco , Presotto Fabio 
Published: January 2014

Abstract
Adrenal cortex autoantibodies (ACA) were measured by immunofluorescence in 808 children with organ-specific autoimmune diseases without adrenal insufficiency. ACA were found in 14 children (1.7%), mostly in hypoparathyroidism (48%). Ten ACA-positive and 12 ACA-negative children were followed up for a maximum of 10 yr by evaluation of adrenocortical function (ACTH test) and autoantibody status. In all patients steroid-producing cell autoantibodies were assessed by immunofluorescence and autoantibodies to steroid 21-hydroxylase, 17α-hydroxylase, and cytochrome P450 side-chain cleavage enzyme by immunoprecipitation assay. All 10 ACA-positive patients were positive for 21-hydroxylase autoantibodies. Six were positive for steroid-producing cell autoantibodies and 5 also for autoantibodies to 17α-hydroxylase and/or P450 side-chain cleavage enzyme. Overt Addison’s disease developed in 9 (90%) ACA/21-OH-antibody-positive children after 3–121 months, and 1 remaining child had subclinical hypoadrenalism. By contrast, all ACA/21-OH antibody-negative children maintained normal adrenal function. Adrenal failure was not related to ACA titres, sex, adrenal function, type of preexisting autoimmune disorder, or human leucocyte antigens D-related status. In conclusion, in children with autoimmune endocrine diseases, ACA/21-hydroxylase autoantibodies are important predictive markers for the development of Addison’s disease.
Adjunctive Growth Hormone during Ovarian Hyperstimulation Increases Levels of Insulin-Like Growth Factor Binding Proteins in Follicular Fluid: A Randomized, Placebo-Controlled, Cross-Over Study*
Authors: Rabinovici Jaron , Cataldo Nicholas A. , Dandekar Pramila , Rosenthal Stephen M. , Gargosky Sharron E. , Gesundheit Neil , Martin Mary C. 
Published: January 2014

Abstract
GH increases circulating insulin-like growth factor I (IGF-I), which can promote the growth and differentiated function of ovarian granulosa and theca cells. Reported studies of GH as an adjunct to menotropin stimulation in women, largely those with ovarian dysfunction, have not consistently shown a benefit of GH, despite increases in serum and follicular fluid IGF-I. We hypothesized that changes in intrafollicular IGF-binding proteins (IGFBPs), which can antagonize IGF actions on granulosa cells, may underlie the inconsistent effects of GH. In the present study of GH, administered in double-blind, placebo-controlled, cross-over fashion to regularly cycling women undergoing in vitro fertilization, we found that follicular fluid levels of IGFBP-1, -3, and -4 and serum levels of IGFBP-3, as well as follicular fluid and serum IGF-I, were significantly increased in the GH-treated cycles, when compared with the placebo cycle of the same patient. We suggest that the net increase in intrafollicular IGFBPs in GH cycles may mitigate the potential beneficial effect of increased IGF-I.
Determination of Testosterone Production Rates in Men and Women Using Stable Isotope/Dilution and Mass Spectrometry*
Authors: Vierhapper H. , Nowotny P. , Waldhäusl W. 
Published: January 2014

Abstract
Production rates of testosterone were determined in healthy men and women during the follicular phase of their menstrual cycle using the stable isotope dilution technique and analysis by gas chromatography/mass spectrometry. In an initial series of experiments, 0.07 mg/h (men) or 0.01 mg/h (women) 1,2-d-testosterone was infused for 36 h. After an equilibration period of 12 h, blood samples were obtained at 20-min intervals throughout 24 h. In men, no diurnal rhythmicity of testosterone production was observed, whereas in women, testosterone production rates were largest from 0400–1200 h. In a second series of experiments, the infused dose of 1,2-d-testosterone was reduced to 0.015 mg/h (men) and 0.0001 mg/h (women), respectively. Blood samples were obtained at 20-min intervals during the last 12 h (0800–2000 h) of the observation period. In accordance with results obtained by others using radioactive tracers, estimated production rates were 147 ± 31μ g/h (3.7 ± 2.2 mg/day in men) and 1.8 ± 0.6 μg/h (0.4 ± 0.1 mg/day in women). To reduce both the duration of the experiment and the number of samples to be processed, we subsequently demonstrated that similar production rates may be obtained when the equilibration period before blood sampling is reduced to 6 h and the period of blood sampling is reduced to 4 h. This protocol is suitable for clinical use in a routine setting to obtain analytically correct estimates of testosterone production in vivo.
Aromatase Deficiency in a Female Who Is Compound Heterozygote for Two New Point Mutations in the P450arom Gene: Impact of Estrogens on Hypergonadotropic Hypogonadism, Multicystic Ovaries, and Bone Densitometry in Childhood1
Authors: Mullis Primus E. , Yoshimura Noriko , Kuhlmann Beatrice , Lippuner Kurt , Jaeger Philippe , Harada Hobuhiro 
Published: January 2014

AbstractWe report on a female who is compound heterozygote for two new point mutations in the CYP19 gene. The allele inherited from her mother presented a base pair deletion (C) occurring at P408 (CCC, exon 9), causing a frameshift that results in a nonsense codon 111 bp (37 aa) further down in the CYP19 gene. The allele inherited from her father showed a point mutation from G-&gt;A at the splicing point (canonical GT to mutational AT) between exon and intron 3. This mutation ignores the splice site and a stop codon 3 bp downstream occurs.Aromatase deficiency was already suspected because of the marked virilization occurring prepartum in the mother, and the diagnosis was confirmed shortly after birth. Extremely low levels of serum estrogens were found in contrast to high levels of androgens. Ultrasonographic follow-up studies revealed persistently enlarged ovaries (19.5–22 mL) during early childhood (2 to 4 yr) which contained numerous large cysts up to 4.8 × 3.7 cm and normal-appearing large tertiary follicles already at the age of 2 yr. In addition, both basal and GnRH-induced FSH levels remained consistently strikingly elevated. Low-dose estradiol (E2) (0.4 mg/day) given for 50 days at the age of 36/12 yr resulted in normalization of serum gonadotropin levels, regression of ovarian size, and increase of whole body and lumbar spine (L1-L4) bone mineral density. The FSH concentration and ovarian size returned to pretreatment levels shortly (150 days) after cessation of E2 therapy. Therefore, we recommend that affected females be treated with low-dose E2 in amounts sufficient to result in physiological prepubertal E2 concentrations using an ultrasensitive estrogen assay. However, E2 replacement needs to be adjusted throughout childhood and puberty to ensure normal skeletal maturation and adequate adolescent growth spurt, normal accretion of bone mineral density, and, at the appropriate age, female secondary sex maturation.
Neonatal Hypothyroxinemia: Effects of Iodine Intake and Premature Birth1
Authors: Ares Susana , Escobar-Morreale Héctor F. , Quero José , Durán Socorro , Presas María Jesus , Herruzo Rafael , Morreale de Escobar Gabriella 
Published: January 2014

AbstractWe have investigated the effects of iodine (I) intake on urinary I excretion in preterm (PT) babies up to 2 months after birth and its effect on serum T4, free T4 (FT4), T3, TSH, and thyroglobulin (Tg) levels compared to those in term (T) newborns.Very premature and very sick infants were in negative I balance for the first weeks after birth. Later, these same infants, as well as the other PT and T newborns, were in positive balance; 75–80% of the ingested I was not accounted for in the urine. The urinary I levels of PT and T neonates cannot be equated to their I intakes.T4, FT4, and T3 levels in PT and T neonates increased with postmenstrual age, whereas Tg decreased and TSH did not change. Serum FT4, T3, Tg, and TSH levels in PT neonates were affected negatively, independently from age, by a low I intake. PT birth also affected T4, FT4, and Tg negatively, independently from I intake and postmenstrual age, for at least 6–8 weeks after birth.Care should be taken to avoid I deficiency in PT neonates. However, even when I intake is adequate, PT newborns are hypothyroxinemic compared to T babies during an important period of brain development. This suggests the possible convenience of interventions that might mimic the intrauterine hormone environment and accelerate maturation.
The Death of Osteocytes via Apoptosis Accompanies Estrogen Withdrawal in Human Bone*
Authors: Tomkinson A. , Reeve J. , Shaw R. W. , Noble B. S. 
Published: January 2014

AbstractEstrogen withdrawal in women leads initially to rapid bone loss caused by increased numbers or activity of osteoclasts. We previously have noted apoptosis of lacunar osteocytes associated with conditions of high bone turnover. Therefore, in this study, we investigated whether the increased bone loss associated with GnRH analogue (GnRH-a)-induced estrogen withdrawal affects osteocyte viability in situ in a way that would be directly contrary to the effect of estrogens on osteoclast viability.Transiliac biopsies were obtained from six premenopausal women, between 30–45 yr old, diagnosed as having endometriosis. Biopsies were taken before and after 24 weeks of GnRH-a therapy. Biopsies were snap-frozen and cryostat sectioned. Osteocyte viability, determined by the presence of lactate dehydrogenase (LDH) activity, was reduced in all but one subject after treatment. Furthermore, in every subject, the proportion of osteocytes showing evidence of DNA fragmentation typical of apoptosis increased, as demonstrated using in situ DNA nick translation (P = 0.008). Gel electrophoresis of extracted DNA and morphological studies of chromatin condensation and nuclear fragmentation confirmed that changes typical of apoptosis were affecting the osteocytes.It was concluded that GnRH-a therapy caused a higher prevalence of dead osteocytes in iliac bone, probably caused by the increase in the observed proportion of osteocytes showing apoptotic changes. The capacity of bone to repair microdamage and to modulate the effects of mechanical strain is currently believed to be dependent on osteocyte viability. Our findings have therefore revealed a possible mechanism whereby estrogen deficiency could lead to increased bone fragility with or without an accompanying net bone loss.
Effects of the Circadian Variation in Serum Cortisol on Markers of Bone Turnover and Calcium Homeostasis in Normal Postmenopausal Women1
Authors: Heshmati Hassan M. , Riggs B. Lawrence , Burritt Mary F. , McAlister Carol A. , Wollan Peter C. , Khosla Sundeep 
Published: January 2014

Bone turnover has a circadian pattern, with bone resorption and, to a lesser extent, bone formation increasing at night. Serum cortisol also has a circadian pattern and is a potential candidate for mediating the circadian changes in bone turnover. Thus, we measured bone formation and resorption markers before (study A) and after (study B) elimination of the morning peak of cortisol. We also assessed effects of the circadian cortisol pattern on serum calcium, PTH, and urinary calcium excretion. Ten normal postmenopausal women, aged 63–75 yr (mean, 69 yr), were studied. Metyrapone was administered to block endogenous cortisol synthesis and either a variable (study A) or a constant (study B) infusion of cortisol was given to reproduce and then abolish the morning cortisol peak. Blood was sampled every 2 h for serum cortisol, ionized calcium, PTH, and bone formation markers[ osteocalcin and carboxyl-terminal propeptide of type I collagen (PICP)], and timed 4-h urine samples were collected for measurement of calcium, phosphorus, sodium, potassium, and bone resorption markers (N-telopeptide of type I collagen and free deoxypyridinoline).During study A, serum osteocalcin had a circadian pattern, with a peak at 0400 h and a nadir at 1400 h. During study B, however, the afternoon nadir of serum osteocalcin was eliminated (P &lt; 0.001 and P &lt; 0.005 for the difference in the patterns of peak and nadir, respectively, on the 2 study days). In contrast, the circadian patterns of serum PICP and urinary N-telopeptide of type I collagen and free deoxypyridinoline were virtually identical during the two studies. Urinary calcium excretion declined after the cortisol peak, without differences between the 2 study days in phosphorus or sodium excretion or in serum PTH. We conclude that the circadian variation in serum cortisol is responsible for the circadian pattern of serum osteocalcin, but not that of PICP or bone resorption markers. The physiological variation in serum cortisol may also reduce urinary calcium excretion.
Increased CD69 and Human Leukocyte Antigen-DR Expression on T Lymphocytes in Insulin-Dependent Diabetes Mellitus of Long Standing
Authors: Gessl Alois , Waldhäusl Werner 
Published: January 2014

To better define prevailing activation of circulating T cell subsets in insulin-dependent diabetes mellitus (IDDM) of recent onset (DM; n= 31; median age ± sd,, 28 ± 6.9 yr) and of long standing (DML; n = 27; age, 33 ± 10.4 yr; median duration of disease, 105 months), CD4+ and CD8+ T cells were analyzed to determine their naive and memory subsets as well as their expression of human leukocyte antigen (HLA)-DR, interleukin-2 receptor α-chain (CD25), and CD69 by three-color flow cytometry. Twenty-six healthy subjects (HS; age, 32.0 ± 8.2 yr) served as controls.No deviation was seen in either IDDM group compared to HS in CD25 expression on CD4+ or CD8+ cells or in their CD45RA+ or CD45RA− subsets. HLA-DR expression, however, was increased (P &lt; 0.05) in total CD8+ cells and CD45RA+ cells, with CD45RA− CD8+ cells joining the prevailing pattern only in DML. Among CD4+ cells, increased expression of HLA-DR molecules was restricted to total and CD45RA− cells in DML. CD69 expression did not differ between IDDM and HS, but differed between DML (CD4+, CD8+, and CD45RA− CD4+) and DM only.In conclusion, our data demonstrate that HLA-DR expression in IDDM is restricted to memory cells (CD45RA−) among CD4+ cells in DML and is more markedly confined to naive (CD45RA+) than to memory CD8+ cells, whereas the early activation antigen CD69 is more readily expressed in DML than in DM. The observed activation of circulating T cells suggests an ongoing immune process in IDDM both at clinical manifestation and after long duration.
Androgen Receptor Gene Expression in the Primate Ovary: Cellular Localization, Regulation, and Functional Correlations
Authors: Weil S. J. , Vendola K. , Zhou J. , Adesanya O. O. , Wang J. , Okafor J. , Bondy C. A. 
Published: January 2014

Excess androgens are associated with a characteristic polyfollicular ovarian morphology; however, it is not known to what extent this problem is due to direct androgen action on follicular development vs. interference with gonadotropin release at the level of the pituitary or hypothalamus. To elucidate potential androgen effects on the ovary, we investigated the cellular localization of androgen receptor (AR) messenger ribonucleic acid (mRNA) in rhesus monkey using in situ hybridization. To investigate the regulation of ovarian AR gene expression, we compared the relative abundance of AR transcripts in monkeys during follicular and luteal phases of the menstrual cycle and in monkeys treated with testosterone. To assess potential functional consequences of AR expression in the primate ovary, we compared AR mRNA levels with indexes of follicular cell proliferation and apoptosis in serial sections from individual follicles.
AR mRNA expression was most abundant in granulosa cells of healthy preantral and antral follicles in the primate ovary. Theca interna and stromal cells also expressed AR mRNA, but to a lesser degree than granulosa cells. No significant cycle stage effects were noted in AR mRNA levels; however, larger numbers of animals would be necessary to definitively establish a cycle stage effect. AR mRNA level was significantly increased in granulosa cells and was decreased in theca interna and stromal cells of testosterone-treated monkeys. Importantly, granulosa cell AR mRNA abundance was positively correlated with expression of the proliferation-specific antigen Ki-67 (r = 0.91; P &lt; 0.001) and negatively correlated with granulosa cell apoptosis (r = −0.64; P &lt; 0.001).
In summary, these data show that primate ovary AR gene expression is most abundant in granulosa cells of healthy growing follicles, where its expression is up-regulated by testosterone. The positive correlation between granulosa AR gene expression and cell proliferation and negative correlation with programmed cell death suggests that androgens stimulate early primate follicle development.