bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping Genes for Polygenic Disorders: Considerations for Study Design in the Complex Trait of Inflammatory Bowel Disease
Authors: Hampe Jochen , Wienker Thomas , Nürnberg Peter , Schreiber Stefan 
Published: April 2003

While the methodology for the mapping of Mendelian disorders is well established, the practical and theoretical steps required for successful gene identification in a complex trait are still difficult to predict. A number of analytical models and simulations based on repetitive drawings from predefined statistical distributions are available. To supplement these analytical models, we developed an integrated simulation approach by directly simulating entire populations under a disease model based on epidemiological data. Random mating, nonoverlapping populations and the absence of differential fitness were assumed. Samples were drawn from these homogeneous and heterogeneous populations and analyzed with established analysis tools. We investigated the properties of linkage and association studies in inflammatory bowel disease – modeled as a six-locus polygenic disorder – as an example of this approach. In nonparametric linkage studies, lod scores varied widely, with the median required sample size depending on the locus-specific relative sibling risk. A fine mapping resolution <4 cM was found to require nonparametric lod scores >10. Family-based association studies (TDT test) and case-control studies showed a similar sensitivity and can identify risk loci in populations with moderate levels of linkage disequilibrium in sample sizes of 500–800 triplets. Case-control association studies were prone to false-positive results if applied in heterogeneous populations, with the false-positive rate increasing with sample size because population heterogeneity is detected with increasing power.
Allele-Specific Variation in the Gene Copy Number of Human <i>Cytosine 5-Methyltransferase</i>
Authors: Franchina Maria , Kay Peter H. 
Published: April 2003

Previously, we have identified two alternate allelic forms of <i>cytosine 5-methyltransferase, 5-MT I</i> and <i>5-MT II</i>, specified by polymorphic fragments of 1.5 and 1.1 kb, respectively. In the presence study, a 0.8-kb genomic probe was prepared which was confirmed to be included within the polymorphic fragments. The 0.8-kb probe hybridised with greater intensity to the 1.1-kb fragment than the 1.5-kb fragment. Densitometric analysis indicated that there is 1 copy of <i>5-MT</i> associated with <i>5-MT I</i>, whereas there may be 1–4 copies of the gene associated with the <i>5-MT II</i> allele. Segregation studies demonstrated that the multiple copies of <i>5-MT II</i> are inherited in a Mendelian fashion. These results allow novel approaches to investigating the underlying mechanisms of cytosine methylation and gene duplication.
Physical and cDNA Mapping in the <i>DBH</i> Region of Human Chromosome 9q34
Authors: Gilbert J.R. , Kumar A. , Newey S. , Rao N. , Ioannou P. , Qiu H. , Lin D. , Xu P. , Pettenati M.J. , Pericak-Vance M.A. 
Published: April 2003

Chromosome 9q34 has been extensively studied and mapped due to the presence of known disease genes, principally tuberous sclerosis 1 (TSC1), in this region. During the course of our mapping of this region we constructed a 555-kb contig beginning approximately 50 kb proximal to the dopamine-β-hydroxylase (DBH) gene and extending, with one small deletion, distal to the D9S114 marker. The contig consists of 11 P1 clones, four PAC clones, one BAC clone and six cosmid clones and contains 27 new nonpolymorphic STSs. We have found the region to be unstable in P1, PAC and BAC cloning vehicles and have identified several deleted genomic clones. In addition, we have isolated and mapped the 3′ portions of three putative genes located within or immediately distal to the DBH gene, including one large gene that runs on the opposite strand to DBH and utilizes portions of two DBH exons. The genomic clones of the contig, cDNAs and new STSs will be useful reagents for the further study and mapping of this region.
Influence of Minor Increases in Plasma Catecholamines on Natural Killer Cell Activity
Authors: Kappel Mogens , Poulsen Troels D. , Galbo Henrik , Pedersen Bente K. 
Published: April 2003

This study was designed to test the hypothesis that the modulations of the human immune system in relation to in vivo whole body hyperthermia may be ascribed to elevations in the plasma epinephrine and norepinephrine concentrations. In a single-blind, controlled, cross-over study, 8 healthy volunteers were selectively infused norepinephrine and epinephrine, respectively, for 1 h, in order to obtain twofold increases in the plasma concentrations of these hormones, thereby mimicking the increases seen during in vivo whole body hyperthermia. Epinephrine infusion increased baseline, interleukin-2 and interferon-α stimulated natural killer cell activity, and the percentage and concentration of cluster designation (CD)16+ cells, whereas the neutrophil and lymphocyte count or the CD3+, CD4+, CD8+, CD19+ and CD14+ cell subtypes were not influenced. Norepinephrine infusion did not cause any changes in these variables. It is concluded that epinephrine, but not norepinephrine, may be responsible for the hyperthermia-induced effects on natural killer cells.
Evaluation of Glucose Tolerance and Insulin Secretion in Cystic Fibrosis Patients
Authors: Peraldo Massimo , Fasulo Adele , Chiappini Elena , Milio Claudia , Marianelli Lore 
Published: April 2003

Blood glucose profile and insulin levels during the oral glucose tolerance test were retrospectively analyzed in 52 cystic fibrosis (CF) patients aged 10–33 years (mean 18 years). Thirty-seven subjects (71.1%) had normal glucose tolerance; 6 patients (11.5%) had impaired glucose tolerance and 9 patients (17.3%), with fasting blood glucose levels below 7.2 mmol/l were classified as diabetic, according to WHO diagnostic criteria. No significant differences in the total amount of secreted insulin (expressed as area under the curve) were detected in CF patients with or without glucose intolerance, but a significant delay in the insulin peak time appeared to be related to a compromised nutritional status. Our data indicate a significantly increased risk of glucose metabolism impairment related to poor nutritional condition (RR 5.40; 95% CI: 1.5–19.7) and worse clinical status (RR 4.27; 95% CI: 1.05–17.2). In particular, glucose tolerance abnormalities were found in 50% of CF patients with an unsatisfactory nutritional condition versus 15.6% of CF patients with good nutritional status. Conclusions: Since CF-related diabetes is often underdiagnosed and associated with deterioration in patients’ overall clinical status, it is very important to identify subjects at risk of developing diabetes by strict monitoring of glucose metabolism when deterioration in nutritional and clinical conditions is seen which cannot be otherwise explained.
Gonadotropin Pulsations across Development
Authors: Hayes Frances J. , Crowley Jr. William F. 
Published: April 2003

Initiation and maintenance of the reproductive axis in the human is contingent upon the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. In man, tracking endogenous GnRH secretion relies on frequent peripheral sampling of three glycoprotein products of the gonadotrope, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and free α-subunit (FAS). FAS is superior to LH as a surrogate marker of GnRH secretory dynamics in those circumstances where GnRH secretion is rapid or where the pituitary LH response is low. The pattern of GnRH secretion is constantly changing across development; from high levels during the neonatal period, through a period of quiescence in mid-childhood, followed by sleep-entrained reactivation of the reproductive axis at the onset of puberty, ultimately culminating in the adult pattern of pulsatile secretion which in the male is approximately every 2 h and in the female varies with the stage of the menstrual cycle. This episodic mode of secretion allows differential impact of feedback mechanisms on the GnRH neurons and facilitates the maintenance of the reproductive axis during periods of stress by allowing frequency and amplitude modulations.
Effect of Cell Density on Hormonal Secretion from Human Pituitary Adenomas in vitro
Authors: Atkin Stephen L. , Hipkin Leslie J. , Landolt Alex M. , Jeffreys Richard V. , Foy Patrick M. , White Michael C. 
Published: April 2003

Cell density effects were investigated on tumorous hormonal secretion from 10 pituitary adenomas: 3 somatotrophinomas secreting GH and PRL; 7 gonadotrophinomas, 3 co-secreted both FSH and LH, all 7 secreted LH. Enzymatically dispersed tissue was plated out in 24-well plates at 5 ×10<sup>5</sup>, 10<sup>5</sup>, 5 ×10<sup>4</sup> and 10<sup>4</sup> cells/well in serum-free media. Media were collected weekly for 2 weeks. <b>Results:</b> In 3 of 3 somatotrophinomas, GH and PRL secretion was higher (p < 0.05) at both week 1 and 2 from 10<sup>4</sup> cells/well, but similar at other cell densities. In all 3 gonadotrophinomas, the FSH secretory rate was highest at 5 ×10<sup>5</sup> cells/well which fell as cell density decreased. Conversely, in 7 of 7 gonadotrophinomas the LH secretory rate was highest at 10<sup>4</sup> cells/well (p < 0.01) which fell as cell density increased. <b>Conclusion:</b> These data suggest that paracrine factors may modulate tumorous GH, PRL, FSH and LH secretion, and show that FSH and LH secretion vary inversely as cell density increases.
Radioiodine Treatment of Graves’ Disease in Young People
Authors: Cheetham T.D. , Wraight P. , Hughes I.A. , Barnes N.D. 
Published: April 2003

In Europe young patients with Graves’ disease are usually treated with antithyroid drugs initially, then if hyperthyroidism recurs after a prolonged course of such medication, they are offered definitive treatment by subtotal or total thyroidectomy. Neither of these forms of treatment is free from problems. Impressed with the simplicity and safety record of radioiodine therapy, we have treated 8 young patients with radioiodine. The patients all presented with typical Graves’ disease and relapsed after 18–24 months of treatment with antithyroid drugs. They were then given the option of a further course of antithyroid medication or definitive treatment with radioiodine or surgery. Those who opted for radioiodine were treated with <sup>131</sup>iodine in a dose of 300 MBq with the intention of ablating the thyroid. Antithyroid medication was resumed for 4–6 months and then withdrawn. Four patients became hypothyroid after a single dose of radioiodine but 4 needed a second dose. All became hypothyroid within 2 years. No adverse effects were observed, in particular no patient showed any deterioration in their eye disease. Radioiodine offers a simple, effective and inexpensive method of treatment for Graves’ disease in young patients. There are no immediate adverse effects and, although some theoretical concerns remain, to date the long-term safety record of thyroid ablation is excellent and the potential risks seem to us to be outweighed by the advantages. Even when a moderately high initial dose of radioiodine is used, a second dose may be needed.
Congenital Hypothyroidism Screening in the West Bank: A Test Case for Screening in Developing Regions
Authors: Sack Joseph , Feldman Inbar , Kaiserman Igor 
Published: April 2003

Screening for congenital hypothyroidism (CH) among the Arab population of the West Bank began in May 1987 as part of the neonatal screening program in Israel. In the West Bank many infants are born at home or are released from the hospital on the 1st day after birth and thus cannot be screened. However, we tried to reach the infants before the age of 1 month at the maternal and child health centers, where they receive immunization. In this screening program, 64% of the infants were sampled by the 1st week and 93% by 3 weeks of life. In contrast to the screening in Israel, where thyroxine determination is followed by thyroid-stimulating hormone measurement, in the West Bank thyroid-stimulating hormone was tested first in order to decrease the recall rates. From June 1990 to February 1994, 49,694 infants were screened in the West Bank, of whom 24 with CH were detected (an incidence of 1:2,070). From January 1987 to February 1994, 28,938 infants were screened in East Jerusalem, of whom 20 with CH were detected (incidence 1:1,447). There were differences between the incidence rates in the various districts. The incidence rates were higher than those reported from industrialized countries, but similar to those found in Saudi Arabia. This may be due to the high degree of consanguineous marriages among Arab populations and to environmental factors. In conclusion, in spite of the many difficulties, both practical and political, CH screening in the West Bank is feasible. Although screening all newborns shortly after birth is not possible, this study shows that a high percentage of them can be screened at a time when they can still be effectively treated. Our results could be used in due time as a baseline for a future independent screening program.
Lumbar Spine Bone Mineral Density in Diabetic Children with Recent Onset
Authors: De Schepper J. , Smitz J. , Rosseneu S. , Bollen P. , Louis O. 
Published: April 2003

To detect early abnormalities in bone mineralization, the lumbar spine bone mineral density (BMD) of diabetic children with a diabetes onset of less than 5 years and treated with a similar insulin treatment scheme was measured at the level of the lumbar spine by dual-energy X-ray absorptiometry (DEXA), a most sensitive technique for detecting osteopenia in children. Fifteen male and 8 female children and adolescents (mean age ± SD: 12.5±3.7 years), 1–5 years after the clinical onset of their diabetes, were studied. Measurements of the lumbar spine (L<sub>1</sub>–L<sub>4</sub>) BMD, expressed in gHA/cm<sup>2</sup> and as a z-score for age, were performed with a commercial DEXA apparatus (Hologic QDR 1000 W, Hologic Inc., Waltham, USA). Calcium-phosphorus metabolism was studied by measuring the circulating levels of calcium, phosphorus, alkaline phosphatase, osteocalcin, 25-OH-vitamin D and parathyroid hormone and the urinary excretion of calcium and phosphorus. The mean BMD of the studied group was 0.75 (0.16) gHA/cm<sup>2</sup> giving a mean z-score of –0.31±0.95. Only 1 of the patients had a BMD lower than –2 SD. No sex difference in BMD z-score existed. BMD SD was positively correlated with height SD (R = 0.56, p < 0.005), but not with the age of the patients, the duration of the disease, the degree of metabolic control or the studied parameters of the calcium-phosphorus metabolism. In conclusion, diabetic children have a normal lumbar spine BMD during the first years of the disease, when a good metabolic control and no abnormalities in the calcium-phosphorus metabolism are present. As in normal children, areal BMD by DEXA is highly dependent on the body height, necessitating corrections if abnormalities in skeletal growth or pubertal development exist.
Response of the Free Alpha-Subunit to GnRH Distinguishes Individuals with ‘Functional’ from Those with Permanent Hypogonadotropic Hypogonadism
Authors: Mainieri Alberto Scofano , Viera José Gilberto H. , Elnecave Regina Helena 
Published: April 2003

The aim of this study was to compare the responses of pituitary gonadotropins and the free α-subunit (FAS), measured by sensitive immunofluorometric assays at 0, 30 and 60 min after 100 µg GnRH i.v. in a group of 32 normal prepubertal boys (NB) and a group of 17 adult males with complete hypogonadotropic hypogonadism (HH). At time 0 min, medians of the serum levels of LH, FSH and FAS were not different in both groups. At 30 min (29.81 and 8.56 pmol/l) and 60 min (24.10 and 7.74 pmol/l) as well as peak levels (29.76 and 8.56 pmol/l), ‘deltas’ (peak minus baseline; 25.89 and 0.34 pmol/l) and ‘fold’-increase (peak divided by baseline; 7.0-fold and 1.6-fold), the medians were significantly higher in NB than in HH, respectively. There were fewer overlapping values of FAS between the 2 groups and they occurred in only 4% of the total number of subjects when ‘fold’ was considered. The measurement of FAS by a very sensitive immunofluorometric assay, after GnRH, distinguishes responses of NB from those of adult men with HH, that is of functional from permanent HH.
Nocturnal TSH Surge and TRH Test Response in the Evaluation of Thyroid Axis in Hypothalamic Pituitary Disorders in Childhood
Authors: Gruñeiro-Papendieck Laura , Chiesa Ana , Martínez Alicia , Heinrich Juan Jorge , Bergadá Cesar 
Published: April 2003

We studied, by means of TSH nocturnal secretion and TRH test, 42 children (4.2–19.9 years) with hypothalamic pituitary disorders and 24 healthy euthyroid children (5.7–15.4 years) as control group. Patients were divided according to their serum values of FT<sub>4</sub> in group 1 (n = 27) with FT<sub>4</sub> ≥10.3 pmol/l and group 2 (n = 15) with FT<sub>4</sub> <10.3 pmol/l. TSH was measured by immunoradiometric assay. TSH nadir, TSH peak and TSH surge were calculated. Both groups differed significantly from control group in TSH surge values: group 1 (p < 0.05), group 2 (p < 0.01). TRH test was abnormal in 11/27 patients of group 1 and 10/15 patients of group 2. In group 1, 7 patients had normal tests, 2 had abnormalities in both tests, 9 had only TSH nocturnal surge altered and 9 showed only TRH alterations. All patients of group 2 presented thyroid axis abnormalities. In conclusion, in patients with hypothalamic pituitary disorders with low FT<sub>4</sub>, no further investigation is required to demonstrate thyroid axis alterations, however in patients with normal FT<sub>4</sub>, nocturnal TSH secretion and TRH test may be required to evidence thyroid abnormalities.
Pubertal Growth as a Determinant of Adult Height in Boys with Constitutional Delay of Growth and Puberty
Authors: Rensonnet Claudie , Kanen François , Coremans Christine , Ernould Christian , Albert Adelin , Bourguignon Jean-Pierre 
Published: April 2003

In boys with constitutional delay of growth and puberty, adult height may be inconsistent with parental (target) height. We aimed at studying which period of growth was important to account for adult height being above or below target height. In this retrospective study, adult height measured after 20 years in 39 patients was compared with target height and height data obtained at about 6 and 12 years of age and at diagnosis of delayed puberty (mean 14.6 years). Twenty-eight patients were untreated while 11 received testosterone enanthate (50 or 100 mg/month for 6 months). The growth data from both groups were pooled since they were not different. On average, the adult height standard deviation score (–0.6 ± 0.8, mean ± SD) was similar to target height (–0.5 ± 0.6). There were, however, marked individual differences since adult height varied between 1.7 SD (11 cm) below target height and 1.4 SD (9.5 cm) above target height. Multiple regression analysis showed that the most significant determinant of the difference between adult height and target height was height catch up during puberty (p < 0.002). We conclude that the magnitude of height catch up during puberty is a significant determinant of adult height in boys with constitutional delay of growth and puberty. Thus, optimizing pubertal growth may be a relevant therapeutic aim for adult height in boys with short stature and delayed puberty.
Auxological and Biochemical Evaluation of Pubertal Suppression with the GnRH Agonist Leuprolide Acetate in Early and Precocious Puberty
Authors: Mul D. , de Muinck Keizer-Schrama S.M.P.F. , Oostdijk W. , Drop S.L.S. 
Published: April 2003

We studied the auxological effects of treatment with the GnRH agonist leuprolide acetate (Lucrin<sup>®</sup>) at 3.75 mg/ 28 days in 38 children with early or precocious puberty. We present our newly developed scoring system, the Puberty Suppression Score (PSS), in which clinical and biochemical parameters determine whether suppression was effective. Leuprolide acetate suppressed pubertal development in the majority of cases. During treatment there was a significant correlation between the number of times that PSS was >0 and gain in predicted adult height (PAH) compared to initial prediction at the start of treatment. After 6 months of treatment, ineffective suppression measured by PSS was associated with the magnitude of gain in PAH. We conclude that a leuprolide acetate dosage of 3.75 mg every 28 days effectively suppresses puberty. PSS is helpful in monitoring the suppressive capacity of a GnRH agonist. We recommend to start with leuprolide acetate at 3.75 mg/28 days and to increase the injection frequency or dose in case PSS is >0 after 6 months of treatment.
Diagnosis of ACTH Deficiency
Authors: Rose Susan R. , Lustig Robert H. , Burstein Stephen , Pitukcheewanont Pisit , Broome Dean C. , Burghen George A. 
Published: April 2003

Test sensitivity and accuracy of 250 μg/m<sup>2</sup> ACTH test, 1 μg/m<sup>2</sup> ACTH test, and overnight metyrapone test were evaluated in 158 children at risk for ACTH deficiency. Of 38 given high-dose ACTH, 20 had normal responses to metyrapone and to high-dose ACTH. 14 had low response to metyrapone; of these only 2 had low cortisol response (<550 nmol/l) to high-dose ACTH. Of 120 given low-dose ACTH, 64 had normal responses to metyrapone and to low-dose ACTH. All 24 with low metyrapone response had low or borderline response to low-dose ACTH. The remaining children had an inconclusive metyrapone response. In conclusion, high-dose ACTH misses most diagnoses of ACTH deficiency (21% sensitivity, 100% specificity, 63% accuracy). In contrast, the low dose ACTH test accurately diagnoses 90% of patients with ACTH deficiency (100% sensitivity, 68% specificity). The low-dose ACTH test can serve as an accurate and practical screening test for adequacy of ACTH reserve.
Growth-Suppressive Effect of Intra-Articular Glucocorticoids Detected by Knemometry
Authors: Heuck Carsten , Wolthers Ole D. , Herlin Troels 
Published: April 2003

After one intra-articular injection of 20 mg triamcinolone hexacetonide in the knee, the length of the contralateral lower leg was found to be reduced in 2 boys with juvenile rheumatoid arthritis.
Zinc Supplementation Increases the Level of Serum Insulin-Like Growth Factor-I but Does Not Promote Growth in Infants with Nonorganic Failure to Thrive
Authors: Hershkovitz Eli , Printzman Ludmilla , Segev Yael , Levy Jacov , Phillip Moshe 
Published: April 2003

We investigated in a randomized double-blind placebo-controlled study the effects of zinc supplementation (2 mg/kg/day) for 12 weeks on growth, serum insulin-like growth factor-I (IGF-I) and insulin-like factor binding protein-3 (IGFBP-3) on 3- to 9-month-old infants with nonorganic failure to thrive (NOFTT). 25 infants completed the study, 14 received zinc supplementation (group A), and 11 received placebo (group B). The control group for baseline measurements was composed of 10 age-matched normal growing infants. There were no significant changes in weight for age, length for age, or weight for length during the entire study period in either group A or B. Serum IGF-I levels at baseline were similar in all the groups. After 12 weeks of therapy, serum IFG-I levels increased significantly only in the zinc-supplemented group, from 40.3 ± 7 ng/ml at baseline to 65 ± 8 ng/ml (p < 0.05). There was a marked difference in serum IGF-I levels between the zinc-supplemented group and the placebo group after 12 weeks: 65 ± 8 vs. 49.4 ± 5 ng/ml (p = 0.058, 95% CI of difference 9.88–21.31). No change was demonstrated in serum IGFBP-3 levels in either study group. We conclude that although zinc supplementation increased serum IGF-I levels, it did not improve the growth parameters of infants with NOFTT.